WO2011151789A2 - Aminoalkyl substituted chalcones and analogues and derivatives thereof - Google Patents
Aminoalkyl substituted chalcones and analogues and derivatives thereof Download PDFInfo
- Publication number
- WO2011151789A2 WO2011151789A2 PCT/IB2011/052396 IB2011052396W WO2011151789A2 WO 2011151789 A2 WO2011151789 A2 WO 2011151789A2 IB 2011052396 W IB2011052396 W IB 2011052396W WO 2011151789 A2 WO2011151789 A2 WO 2011151789A2
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- bushrachalcone
- moieties
- designated
- set out
- Prior art date
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- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 235000005513 chalcones Nutrition 0.000 title claims abstract description 54
- 150000001789 chalcones Chemical class 0.000 title claims abstract description 26
- 125000004103 aminoalkyl group Chemical group 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 238000000034 method Methods 0.000 claims abstract description 72
- 239000003814 drug Substances 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 201000004792 malaria Diseases 0.000 claims abstract description 7
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 claims description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 150000001412 amines Chemical group 0.000 claims description 20
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- -1 amine acetate Chemical class 0.000 claims description 18
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 10
- 125000002009 alkene group Chemical group 0.000 claims description 10
- 150000001299 aldehydes Chemical class 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 150000007975 iminium salts Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 8
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 8
- 150000003335 secondary amines Chemical class 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 238000005882 aldol condensation reaction Methods 0.000 claims description 7
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical group CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 238000006683 Mannich reaction Methods 0.000 claims description 5
- 150000004982 aromatic amines Chemical class 0.000 claims description 5
- 150000002206 flavan-3-ols Chemical class 0.000 claims description 5
- 150000003141 primary amines Chemical class 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- CVYNTXBILWATKN-UHFFFAOYSA-N 2-phenyl-4h-chromen-3-one Chemical class O=C1CC2=CC=CC=C2OC1C1=CC=CC=C1 CVYNTXBILWATKN-UHFFFAOYSA-N 0.000 claims description 4
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 claims description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 4
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical group F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 239000001294 propane Substances 0.000 claims description 4
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical group NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 4
- 150000003457 sulfones Chemical group 0.000 claims description 4
- 150000003462 sulfoxides Chemical group 0.000 claims description 4
- 150000003568 thioethers Chemical group 0.000 claims description 4
- 230000001131 transforming effect Effects 0.000 claims description 4
- TXZZTLRVXGOMAB-UHFFFAOYSA-N 2-phenyl-2h-chromene Chemical class C1=CC2=CC=CC=C2OC1C1=CC=CC=C1 TXZZTLRVXGOMAB-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 108010081348 HRT1 protein Hairy Chemical group 0.000 claims description 3
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 3
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 229930182497 flavan-3-ol Natural products 0.000 claims description 3
- 229930003949 flavanone Natural products 0.000 claims description 3
- 235000011981 flavanones Nutrition 0.000 claims description 3
- 229930003944 flavone Natural products 0.000 claims description 3
- 150000002213 flavones Chemical class 0.000 claims description 3
- 235000011949 flavones Nutrition 0.000 claims description 3
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 claims description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical class CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 2
- CITFYDYEWQIEPX-UHFFFAOYSA-N Flavanol Natural products O1C2=CC(OCC=C(C)C)=CC(O)=C2C(=O)C(O)C1C1=CC=C(O)C=C1 CITFYDYEWQIEPX-UHFFFAOYSA-N 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000005487 catechin Nutrition 0.000 claims description 2
- 229950001002 cianidanol Drugs 0.000 claims description 2
- QGGZBXOADPVUPN-UHFFFAOYSA-N dihydrochalcone Chemical compound C=1C=CC=CC=1C(=O)CCC1=CC=CC=C1 QGGZBXOADPVUPN-UHFFFAOYSA-N 0.000 claims description 2
- PXLWOFBAEVGBOA-UHFFFAOYSA-N dihydrochalcone Natural products OC1C(O)C(O)C(CO)OC1C1=C(O)C=CC(C(=O)CC(O)C=2C=CC(O)=CC=2)=C1O PXLWOFBAEVGBOA-UHFFFAOYSA-N 0.000 claims description 2
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 235000011987 flavanols Nutrition 0.000 claims description 2
- 150000002208 flavanones Chemical class 0.000 claims description 2
- 150000002214 flavonoid derivatives Chemical class 0.000 claims description 2
- HVQAJTFOCKOKIN-UHFFFAOYSA-N flavonol Natural products O1C2=CC=CC=C2C(=O)C(O)=C1C1=CC=CC=C1 HVQAJTFOCKOKIN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002216 flavonol derivatives Chemical class 0.000 claims description 2
- 235000011957 flavonols Nutrition 0.000 claims description 2
- 229930182470 glycoside Natural products 0.000 claims description 2
- 150000002338 glycosides Chemical class 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 125000000837 carbohydrate group Chemical group 0.000 claims 5
- 150000001788 chalcone derivatives Chemical class 0.000 claims 2
- 238000001308 synthesis method Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 230000008569 process Effects 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 30
- 238000012360 testing method Methods 0.000 description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 20
- 125000003277 amino group Chemical group 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000003556 assay Methods 0.000 description 14
- 150000002215 flavonoids Chemical class 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 229930003935 flavonoid Natural products 0.000 description 12
- 235000017173 flavonoids Nutrition 0.000 description 12
- 244000045947 parasite Species 0.000 description 10
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 10
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000001203 anti-plasmodial effect Effects 0.000 description 8
- 229960003677 chloroquine Drugs 0.000 description 8
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 8
- 241000223960 Plasmodium falciparum Species 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 5
- 150000001720 carbohydrates Chemical group 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- SXQCTESRRZBPHJ-UHFFFAOYSA-M lissamine rhodamine Chemical compound [Na+].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S([O-])(=O)=O)C=C1S([O-])(=O)=O SXQCTESRRZBPHJ-UHFFFAOYSA-M 0.000 description 5
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
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- 230000002401 inhibitory effect Effects 0.000 description 4
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- 239000002904 solvent Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 230000009036 growth inhibition Effects 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
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- 231100000002 MTT assay Toxicity 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
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- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
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- DGZIDJRJAQESTL-UHFFFAOYSA-N 3-[4-hydroxy-3-(morpholin-4-ylmethyl)phenyl]-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound COc1ccc(cc1)C(=O)C=Cc1ccc(O)c(CN2CCOCC2)c1 DGZIDJRJAQESTL-UHFFFAOYSA-N 0.000 description 1
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- VXILEDCHUJDOBG-VZUCSPMQSA-N CN(C)Cc(ccc(/C=C/C(c(cc1)ccc1OC)=O)c1)c1O Chemical compound CN(C)Cc(ccc(/C=C/C(c(cc1)ccc1OC)=O)c1)c1O VXILEDCHUJDOBG-VZUCSPMQSA-N 0.000 description 1
- CQHKAKFNOIPDRN-YCRREMRBSA-N COc(cc1)ccc1C(/C=C/c1cc(O)c(CN2CCOCC2)cc1)=O Chemical compound COc(cc1)ccc1C(/C=C/c1cc(O)c(CN2CCOCC2)cc1)=O CQHKAKFNOIPDRN-YCRREMRBSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- OEIJRRGCTVHYTH-UHFFFAOYSA-N Favan-3-ol Chemical compound OC1CC2=CC=CC=C2OC1C1=CC=CC=C1 OEIJRRGCTVHYTH-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- TUMBTXSGFTVGFD-UHFFFAOYSA-N [2-(3-oxo-3-phenylprop-1-enyl)phenyl] acetate Chemical compound CC(=O)OC1=CC=CC=C1C=CC(=O)C1=CC=CC=C1 TUMBTXSGFTVGFD-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 150000002207 flavanone derivatives Chemical class 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011546 protein dye Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C225/18—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings the carbon skeleton containing also rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/14—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention relates to B-ring aminoalkyi substituted chalcones and analogues thereof. It also relates to processes for the synthesis of such compounds and to the use of such compounds as medicaments, in particular but not exclusively for the treatment of cancer and malaria.
- a chalcone is defined as a molecule that consists of two aromatic rings linked by a carbonyl and an alkene group.
- the convention is followed of referring to the aromatic ring structure adjacent the carbonyl group as the A ring and to the aromatic ring adjacent the alkene group as the B ring.
- the carbonyl group and the alkene double bond are conjugated with each other and with the two aromatic rings, one on either side thereof.
- the aromatic rings are normally hydroxylated aromatic rings i.e. substituted by one or more hydroxy groups.
- the hydroxy group or groups may be further fully or selectively derivatised to methyl or benzyl ethers or acetates.
- the aromatic rings may in addition to, or instead of one or more of the hydroxy groups, also be substituted with one or more CF 3 , halide, a C1 to C6 alkyl group such as a methyl group, an added sugar group such as glucose, fructose or ribose group or groups.
- Chalcones can be prepared by an aldol condensation between a benzaldehyde and an acetophenone in the presence of sodium hydroxide as a catalyst. Chalcones always have three carbons between the two aromatic rings, one a carbonyl carbon and the other two alkene carbons. The alkene double bond, when present, is always conjugated with the carbonyl group. They are thus 1 ,3-Diaryl-2- propen-1-ones.
- the present invention provides compounds designated by the arbitrary collective name of bushrachalcones which compounds are B-ring aminoalkyi substituted chalcones, analogues of chalcones and derivatives of such chalcones.
- Bushrachalcones as defined herein may accordingly be in either a chalcone form or in the form of an analogue of a chalcone, and in particular, but not only, flavonoid analogues of chalcones, and their derivatives.
- an amine moiety typically morpholine and
- a carbon moiety typically CH 2 , linking the B-ring of the chalcone to the amine moiety.
- the amine moiety is linked at its nitrogen to the B-ring of the chalcone via a carbon-atom.
- Bushrachalcones thus include B-ring aminoalkylated chalcones with an aminoalkyi substituent on the B-ring of the chalcone.
- Flavonoids may be derived from chalcones via cyclisation between a 2-hydroxy substituent on the A-ring of the chalcone and the alkene moiety of the chalcone. This cyclisation creates a five or six membered heterocyclic ring, conventional! designated the C-ring. Whether the C-ring is a 5 or 6 membered ring depends on which alkene carbon binds to the 2-hydroxy during the cyclysation. Only chalcones with a 2-hydroxygroup on the A-ring can be converted to flavonoids. It is also possible to prepare flavonoids by other methodologies which do not proceed via the cyclysation of chalcones. Flavonoids so prepared are also notionally considered to be analogues or derivatives of chalcones.
- an amine moiety typically morpholine and
- F R7, Rs, R9, R10, R16 and R is an aminoalkyl substituent of the general
- each of R and R12 is independently selected from the group consisting of -H, -OH, halogens, oxygen, Ci-Ce hydrocarbyl groups, saccharide moieties and -OR18 wherein R « is selected from the group consisting of -H and a Ci to Ce hydrocarbyl group;
- each of R13, R14 and R15 is independently selected from the group consisting of -H, -OH, halogens, C1-C6 hydrocarbyl groups, saccharide moieties and -OR18 wherein R 8 is selected from the group consisting of -H and a Ci to Ce hydrocarbyl group so that the nitrogen may be selected from a primary, secondary, tertiary or quaternary amine, an amine oxide and an amine acetate; or
- Ri 3 Ri 4 (Ris)m are collectively a cyclic amine, including an aromatic amine and also including cyclic amines which include other hetero atoms; and the remainder of each of Ri , R2, R3, R4, Rs, Re, R7, Re.
- R10, R16 and Rn is independently selected from the group consisting of -H, -OH, halogens, CF 3 , CHF2,CH 2 F, nitro moieties, amino moieties (but excluding (7-Chloro-4-quinolinyl)amino), sulfonic moieties, sulphanilamide moieties, cyano moieties, sulphide moieties, sulfoxide moieties, sulfone moieties, phosphonate moieties, phosphate moieties, d- Ce hydrocarbyl moieties, saccharide moieties and -OR13 wherein R-ie is selected from the group consisting of -H, and a Ci to C 6 hydrocarbyl group, with the proviso that when R 7 and R9 are both dimethylaminomethyl groups and R 8 is an
- R 3 and R4 shall not both be -H or -CI or R 3 shall not be -Br when R 4 is -H, and with the further proviso that when R 2 and R4 are both dimethylaminomethyl groups and R3
- R 8 are both hydroxyl groups then at least one of Ri , R 5 , R 6 , R7, R9, R10, Rie and R17 shall not be -H, and analogues and derivatives of a chalcone of Formula 10, and pharmaceutically acceptable salts and solvates of the chalcones, its analogues and derivatives.
- a compound which is a derivative of a chalcone of the Formula 10 which is selected from the group consisting of compounds represented by the general Formula 25a or general Formula 25b
- substituents Ri to R17 are as defined above and R25 is selected from the group consisting of -H, -OH, halogens, CF3, CHF2.CH2F, nitro moieties, amino moieties, sulfonic moieties, sulphanilamide moieties, cyano moieties, sulphide moieties, sulfoxide moieties, sulfone moieties, phosphonate moieties, phosphate moieties, Ci- C 6 hydrocarbyl moieties, saccharide moieties and -ORi 8 wherein Ri 8 is selected from the group consisting of -H, and a Ci to Ce hydrocarbyl group.
- a compound which is an hydrogenated derivative of a compound of Formula 10 in which the carbonyl group between the two aromatic rings is hydrogenated to reduce the compound to a 1 ,3-diaryl-prop-2-ene in which the two aromatic rings are linked by a propene moiety with a 2,3- double bond the analogue compound having a structure as set out in Formula B2
- R6, R7, Re, 9, R10, R16 and R17 in Formula 10 is a hydroxyl group or a derivative of a hydroxy group which hydroxy group or derivative thereof is bound to a carbon adjacent to the carbon on which the alkylamino substituent is bound.
- the invention specifically provides for compound designated as bushrachalcone A, having the formula depicted as Formula A
- the invention also provides a compound designated as bushrachalcone AB having a structure as set out in formula AB
- the invention also provides a compound designated bushrachalcone E having a structure as set out in Formula E
- the invention also provides a compound designated bushrachalcone F having a structure as set out in Formula
- the invention also provides a compound designated bushrachalcone G having a structure as set out in Formula G
- the invention also provides a compound designated bushrachalcone I having a structure as set out in Formula I
- the invention also provides a compound designated bushrachalcone J having a structure as set out in Formula J
- the invention also provides a compound designated bushrachalcone K having a structure as set out in Formula K
- the invention also provides a compound designated bushrachalcone L having a structure as set out in Formula
- the invention also provides a compound designated bushrachalcone M having a structure as set out in Formula M
- the invention also provides a compound designated bushrachalcone N having a structure as set out in Formula N
- the invention also provides a compound designated bushrachalcone P having a structure as set out in Formula P
- the invention also provides a compound designated bushrachalcone R having a structure as set out in Formula R
- the invention also provides a compound designated bushrachalcone S having a structure as set out in Formula
- the invention also provides a compound designated bushrachalcone T having a structure as set out in Formula T
- the invention also provides a compound designated bushrachalcone V having a structure as set out in Formula V
- the invention also provides a compound designated bushrachalcone W having a structure as set out in Formula W
- the invention also provides a compound designated bushrachalcone W1 having a structure as set out in Formula W1
- the invention also provides a compound designated bushrachalcone X having a structure as set out in Formula X
- the invention also provides a compound designated bushrachalcone Z having a structure as set out in Formula
- the invention also provides a compound designated bushrachalcone X1 having a structure as set out i Formula X1
- the invention also provides a compound designated bushrachalcone X2 having a structure as set out in Formula X2
- a method for synthesising a compound according to the invention defined above including the steps of reacting a suitably substituted chalcone with a suitably selected amine moiety of formula AX in the presence of a non-enolizable aldehyde under acidic or basic Mannich reaction conditions, or alternatively treating a suitably substituted aldehyde with an amine moiety of formula AX in the presence of a non-enolizable aldehyde under acidic or basic Mannich reaction conditions and converting the resultant compound to a chalcone, and optionally further derivitising the compound,
- each of Ri 3 , Ru. F1 ⁇ 2 and R20IS independently selected from the group consisting of -H, -OH, halogens, C1-C6 hydrocarbyl groups, saccharide moieties and -OR18 wherein R18 is selected from the group consisting of -H and a Ci to Ce hydrocarbyl group so that the nitrogen may be selected from a primary, secondary, tertiary or quaternary amine, an amine oxide and an amine acetate; or
- (Ri3 i4R2o(Ri5)m) are collectively a cyclic amine, including an aromatic amine and also including cyclic amines which include other hetero atoms.
- the method as defined above is performed with an amine moiety selected from the group consisting of NH 3 or a primary or a secondary amine or cyclic amine or acceptable salt thereof.
- the method according to the invention may be performed with NH 3 , or a primary or secondary amines or cyclic amines which is a hydrochlorides of such compounds.
- the invention further provides for a method for synthesising a compound according to the invention as herein defined wherein the non enolizable aldehyde is beforehand reacted with the NH 3 or primary or secondary amines or cyclic amines or their suitable salts to form an iminium salt, and such preformed salt is then reacted with the chalcone.
- the invention also specifically provides for a method for synthesising bushrachaicone A comprising the steps of preparing a precursor chalcone of Formula B
- the invention provides for a method for synthesising bushrachalcone A comprising the steps of reacting an aminoalkylated acetaldehyde of the structure of Formula D1 with the acetophenone of the structure of Formula C as set out herein under aldol conditions
- the invention also provides a method for synthesising bushrachalcone E comprising the step of treating bushrachalcone A with methyl iodide.
- the invention also provides a method for synthesising bushrachalcone G comprising the step oxidising the benzyl protected form of bushrachalcone A designated bushrachalcone F with hydrogen peroxide or mCPBA to obtain the N-oxide analogue, designated bushrachalcone G as herein defined.
- the invention also provides a method for synthesising bushrachalcone I comprising the step of treating bushrachalcone H with acetic acid anhydride in pyridine.
- the invention also provides a method for synthesising bushrachalcone K comprising the step of cyclising bushrachalcone J.
- the invention also provides a method for synthesising bushrachalcone L comprising the step of deprotecting the hydroxyl group of bushrachalcone J.
- the invention also provides a method for synthesising bushrachalcone N comprising the step of treating bushrachalcone M with piperidine and formaldehyde.
- the invention also provides a method for synthesising bushrachalcone P comprising the step of treating catechin of formula O with dimethylammoniumchloride ((CHs NHCI) in the presence of formaldehyde
- the invention also provides a method for synthesising bushrachalcone R comprising the steps of reacting formaldehyde with dimethylamine to form an iminium salt of the formula Q,
- the invention also provides a method for synthesising bushrachalcone T comprising the step of treating the glycoside of formula S1 with the dimethyl iminium salt of formula Q
- the invention also provides a method for synthesising bushrachalcone V comprising the step of aminoalkylating a-hydroxychalcone of formula U
- the invention also provides a method for synthesising bushrachalcone X comprising the step of transforming bushrachalcone W via a tosyl intermediate of formula W1 into the trifluoromethyl analogue Bushrachalcone X.
- the invention also provides a method for synthesising bushrachalcone Z comprising the step of aminoalkylating compound of formula Y
- the invention also provides a method for synthesising bushrachalcone X1 comprising the step of transforming buschrachalcone X with hydroxylamine . According to a further aspect of the invention it provides for the use of a compound according to the invention as herein defined for the treatment of ailments in animals including man.
- the use may thus be for the treatment of cancer or malaria in animals including man.
- the invention according to a further aspect thereof also provides for a method for the treatment of ailments in animals including man, and in particular the treatment of cancer or malaria, by administering to an animal in need of such treatment a therapeutically effective dose of a compound according to the invention. Further the invention provides for the use of compounds according to the invention as herein described for use in the manufacture of a medicament for use in the treatment of an ailment in animals including man.
- the invention also provides for a pharmaceutical preparation containing a therapeutically effective dose of a compound according to the invention, or part of such dose, in a pharmaceutically acceptable carrier or in combination with one or more pharmaceutically acceptable excipient.
- Flavonoid analogues of bushrachalcone are thus aminoalkylated flavonoids with an aminoalkyl substuent on the B-ring of the flavonoid.
- the amine moiety of the bushrachaikones and flavonoid analogues can be in the N-H, N-oxide, N-alkyl or N-carbonyl form.
- the alkene moiety in the bushrachaikones in chalcone form may be in the Z or E configuration.
- the alkene is normally unsubsituted but can have substituents such as with a hydroxyl or acetoxy group in which case it is an a- or ⁇ - hydroxy- or acetoxychalcone.
- the amine moiety of bushrachalcone may be a primary (NH 2 ), secondary (NHR), tertriary (NR2) or quaternary (NR 3 + ) amine.
- the two or three substituents (R) may be different (e.g. the amine can be R1R2 or RiR2R3 + ) where Ri , R2 and R3 are different. They may however also be the same. Ri and R2 together with the N to which they are bound can also be part of the same moiety in which case they collectively constitute a cyclic amine e.g. piperidine.
- Ri , R 2 and R 3 together with the N to which they are bound may also be aromatic or heterocyclic or both.
- the nitrogen may also have other substituents e.g. it may be acetylated (N-H replaced by N-OAc) or alkylated (e.g. N- H replaced by CH 3 ).
- One or more of the hydroxy groups on the aromatic rings may be replaced by a group that resist enzymatic degradation such as -CF 3 , a halogen, a C1-C6 alkyl group such as a methyl group or added sugar group such as glucose, in which case it is a C-glycoside of a chalcone.
- a group that resist enzymatic degradation such as -CF 3 , a halogen, a C1-C6 alkyl group such as a methyl group or added sugar group such as glucose, in which case it is a C-glycoside of a chalcone.
- bushrachalcone A The presently preferred form the bushrachalcones, herein designated as bushrachalcone A, the amine group is morpholine, and it has the formula depicted as Formula A herein described.
- Bushrachalcone A has been tested by the applicant and found to have good activity against melanoma and malaria.
- the chalkone may be cyclised via the carbonylgroup on C1 and further transformed with retention or migration of the alkenegroup to yield fiavone derivatives of bushrachalcone.
- fiavone derivatives can also be manufactured directly by treating the corresponding flavanone, fiavone or flav-3-ene precursors with an amine in the presence of an aldehyde under acidic or basic annich conditions.
- the amine may be in the form of hydrochloride or other acid salt form or a preformed iminium salt may be used.
- Flavan-3-ol and 3-oxo-flavans can be treated in a similar way to obtain flav-3-ol-amines (formula 7) and 3-oxo-flavan (formula 8) derivatives.
- the aminoalkylated chalcone or other derivatives contain primary, secondary or tertiary amines
- the amine moieties may be alkylated to secondary, tertiary and quaternary amines respectively.
- Primary and secondary amine moieties may also be acetylated to N-acetates or oxidized to amine oxides.
- the amine may be any amine, including aliphatic amines such as methylamine, dimethylamine, ethylamine, diethylamine, cyclohexylamine, amphetamine, cyclic amines such as pipendine, pyrrolidine and aromatic amines such as aniline, benzylamine etc.
- aliphatic amines such as methylamine, dimethylamine, ethylamine, diethylamine, cyclohexylamine, amphetamine, cyclic amines such as pipendine, pyrrolidine and aromatic amines such as aniline, benzylamine etc.
- One or more hydroxy groups of any of the bushrachalcones, chalcone, acetophenone, benzaldehyde or flavones precursor may be protected prior to being coupled to the amine, typically as a benzyl ester or acetate.
- the protecting groups may be removed after the synthesis of the bushrachalcones.
- the diarylpropane e [3-(3-hydroxyphenyl)-1-(4-methoxyphenyl)propane] was synthesized via reduction of the carbonyl group and double bond of a using conventional methods (Pd(OH) 2 /C/H 2 ).
- Ojvdwaw 720 is the bushrachalcone of Formula F
- Ojvdwaw 723 is the bushrachalcone of Formula A.
- test samples were prepared to a 20 mg/ml stock solution in 100% DMSO. Stock solutions were stored at -20° C. Further dilutions were prepared in DMSO and complete medium on the day of the experiment. Samples were tested as a suspension if not completely dissolved. Chloroquine (CQ) was used as the reference drug. A full dose-response was performed to determine the concentration inhibiting 50% of parasite growth (IC 50 -value). Test samples were initially tested at a starting concentration of 100 pg/MI, which was then serially diluted 2-fold in complete medium to give 10 concentrations, with the lowest concentration being 0.2 pg/ml. The same dilution technique was used for all samples.
- CQ Chloroquine
- the MTT-assay is used as a colorimetric assay for cellular growth and survival, and compares well with other available assays (Mosman et al., 1983 and Rubinstein et al., 1990).
- the tetrazolium salt MTT was used to measure all growth and chemosensitivity. The test samples were tested in triplicate on one occasion.
- test samples were prepared to a 20 mg/MI stock solution in 100% DMSO. Stock solutions were stored at -20 °C. Further dilutions were prepared in DMSO and complete medium on the day of the experiment. Samples were tested as a suspension if not completely dissolved. Chloroquine (CQ) was used as the reference drug. A full dose-response was performed to determine the concentration inhibiting 50% of parasite growth (ICso-value). Test samples were initially tested at a starting concentration of 100 pg/MI, which was then serially diluted 2-fold in complete medium to give 10 concentrations, with the lowest concentration being 0.2 pg/MI. The same dilution technique was used for all samples.
- CQ Chloroquine
- the MTT-assay is used as a colorimetric assay for cellular growth and survival, and compares well with other available assays (Mosman et al., 1983 and Rubinstein et al., 1990).
- the tetrazolium salt MTT was used to measure all growth and chemosensitivity.
- the test samples were tested in triplicate on one occasion.
- the sample preparation was the same as for the antiplasmodial testing. Dilutions were prepared on the day of the experiment.
- Emetine was used as the reference drug in all experiments.
- the initial concentration of emetine was 100 ug ml, which was serially diluted in complete medium with 10-fold dilutions to give 6 concentrations, the lowest being 0.001 pg/ml.
- the same dilution technique was applied to all the test samples.
- the highest concentration of solvent (0.5%) to which the cells were exposed to had no measurable effect on the cell viability (data not shown).
- IC50 50% inhibitory concentration
- n number of data sets averaged
- Compounds Ojvdwaw 722, Ojvdwaw 723, OslbAnke4, and OslbAnke 1 showed moderate activity with ICso-values ranging from 1 g/MI to 3 pg/MI. 5.
- SRB Sulforhodamine B
- the SRB assay was developed by Skehan and colleagues to measure drug-induced cytotoxicity and cell proliferation. Its principle is based on the ability of the protein dye sulforhodamine B (Acid Red 52) to bind electrostatically in a pH-dependent manner to protein basic amino acid residues of trichloroacetic acid-fixed cells. Under mild acidic conditions it binds to the fixed cellular protein, while under mild basic conditions it can be extracted from cells and solubilized for measurement.
- the SRB Assay is performed at CSIR in accordance with the protocol of the Drug Evaluation Branch, NCI, and the assay has been adopted for this screen.
- the human cell lines TK10, UACC62 and MCF7 was obtained from NCI in the framework of a collaborative research program between CSIR and NCI. Cell lines was routinely maintained as a monolayer cell culture at 37 °C, 5% CO2, 95% air and 100% relative humidity in RPMI containing 5% fetal bovine serum, 2 mM L-glutamine and 50pg/MI gentamicin.
- the cells (3-19 passages) were inoculated in 96-well microtiter plates at plating densities of 7-10 000 cells/well and were incubated for 24 h. After 24 h one plate was fixed with TCA to represent a measurement of the cell population for each cell line at the time of drug addition (TO).
- the other plates with cells were treated with the experimental drugs which were previously dissolved in DMSO and diluted in medium to produce 5 concentrations (6.25-100 ppm). Cells without drug addition served as control.
- the blank contains complete medium without cells. Etoposide was used as a standard.
- the plates were incubated for 48 h after addition of the compounds. Viable cells were fixed to the bottom of each well with cold 50% trichloroacetic acid, washed, dried and dyed by SRB. Unbound dye was removed and protein- bound dye was extracted with 10 mM Tris base for optical density determination at the wavelength 540 nm using a multiwell spectrophotometer.
- the optical density of the test well after 48-h period of exposure to the test drug is T
- the optical density at time zero is TO
- the control optical density is C.
- the TGI signifies a cytostatic effect.
- TGI total growth inhibition
- the biological activities were separated into 4 categories: inactive (TGI >50 ug/MI or TGI >100 ⁇ ), weak activity (15 pg/MI ⁇ TGI ⁇ 50 pg/MI or 30 ⁇ ⁇ TGI ⁇ 100 ⁇ , moderate activity (6.25 ⁇ 9/ ⁇ ⁇ TGI ⁇ 15 pg/ml or 10 ⁇ ⁇ TGI ⁇ 30 ⁇ and potent activity (TGI ⁇ 6.25 Mg/MI or TGI ⁇ 10 ⁇ ).
- GI50 50% growth inhibition and signifies the growth inhibitory power of the test agent
- TGI which is the drug concentration resulting in total growth inhibition and signifies the cytostatic effect of the test agent
- LC50 50% lethal concentration and signifies the cytotoxic effect of the test agent
- LC100 50% lethal concentration and signifies the cytotoxic effect of the test agent
- Test compound concentration 100 - 0.01 ⁇ (5 x 10-fold serial dilutions)
- the compounds are considered inactive if parameter TGI for two cell lines is higher than 50 pg/ml or 100 ⁇ . Therefore the samples Ojvdwaw 719 and OslbAnke3 can be considered as inactive at the tested concentrations but may well be active at higher concentrations.
- the compounds Ojvdwaw 719 and OslbAnke3 demonstrate higher selectivity at the cell line UACC-62.
- Ojvdwaw 713 and Ojvdwaw 722 can be estimated as weakly active, and OslbAnke 1, OslbAnke 4 and Ojvdwaw 723 can be considered as moderately active .
- the sample Ojvdwaw 720 is active against cell linesTK and potent against cell lines UACC-62 and MCF-7 (values TGI).
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Abstract
This invention relates to B-ring aminoalkyl substituted chalcones and analogues thereof. It also relates to processes for the synthesis of such compounds and to the use of such compounds as medicaments, in particular but not exclusively for the treatment of cancer and malaria.
Description
AMINOALKYL SUBSTITUTED CHALCONES AND ANALOGUES AND DERIVATIVES THEREOF FIELD OF THE INVENTION
This invention relates to B-ring aminoalkyi substituted chalcones and analogues thereof. It also relates to processes for the synthesis of such compounds and to the use of such compounds as medicaments, in particular but not exclusively for the treatment of cancer and malaria.
BACKGROUND TO THE INVENTION
Significant biological activities have been attributed to the classes of compounds known as chalcones and flavonoids. The present invention introduces novel compounds in these classes.
A chalcone is defined as a molecule that consists of two aromatic rings linked by a carbonyl and an alkene group. In this description the convention is followed of referring to the aromatic ring structure adjacent the carbonyl group as the A ring and to the aromatic ring adjacent the alkene group as the B ring. The carbonyl group and the alkene double bond are conjugated with each other and with the two aromatic rings, one on either side thereof. The aromatic rings are normally hydroxylated aromatic rings i.e. substituted by one or more hydroxy groups. The hydroxy group or groups may be further fully or selectively derivatised to methyl or benzyl ethers or acetates. The aromatic rings may in addition to, or instead of one or more of the hydroxy groups, also be substituted with one or more CF3, halide, a C1 to C6 alkyl group such as a methyl group, an added sugar group such as glucose, fructose or ribose group or groups. Chalcones can be prepared by an aldol condensation between a benzaldehyde and an acetophenone in the presence of sodium hydroxide as a catalyst. Chalcones always have three carbons between the two aromatic rings, one a carbonyl carbon and the other two alkene carbons. The alkene double bond, when present, is always conjugated with the carbonyl group. They are thus 1 ,3-Diaryl-2- propen-1-ones.
The present invention provides compounds designated by the arbitrary collective name of bushrachalcones which compounds are B-ring aminoalkyi substituted chalcones, analogues of chalcones and derivatives of such chalcones. Bushrachalcones as defined herein may accordingly be in either a chalcone form or in the form of an analogue of a chalcone, and in particular, but not only, flavonoid analogues of chalcones, and their derivatives.
Bushrachalcones in their chalcone form typically consist of three building blocks:
a chalcone moiety;
an amine moiety, typically morpholine and
a carbon moiety, typically CH2 , linking the B-ring of the chalcone to the amine moiety.
The amine moiety is linked at its nitrogen to the B-ring of the chalcone via a carbon-atom. Bushrachalcones thus include B-ring aminoalkylated chalcones with an aminoalkyi substituent on the B-ring of the chalcone.
Flavonoids may be derived from chalcones via cyclisation between a 2-hydroxy substituent on the A-ring of the chalcone and the alkene moiety of the chalcone. This cyclisation creates a five or six membered heterocyclic ring, conventional! designated the C-ring. Whether the C-ring is a 5 or 6 membered ring depends on which alkene carbon binds to the 2-hydroxy during the cyclysation. Only chalcones with a 2-hydroxygroup on the A-ring can be converted to flavonoids. It is also possible to prepare flavonoids by other methodologies which do not proceed via
the cyclysation of chalcones. Flavonoids so prepared are also notionally considered to be analogues or derivatives of chalcones.
Bushrachatcones in the form of flavonoid analogues of chalcones consist of the following building blocks:
a flavonoid moiety;
an amine moiety, typically morpholine and
a carbon moiety, typically CH2 , linking the B-ring of the flavonoid to the amine moietiey.. DESCRIPTION OF THE INVENTION
According to the invention there is provided a compound which is selected from the chalcones of the general Formula 10
Formula 10
wherein:
at least one of F R7, Rs, R9, R10, R16 and R is an aminoalkyl substituent of the general
Formula AA:
-C(RiiRi2)N(Ri3Ri,(Ri5)m) Formula AA in which
m is a numeral which is either 0 or 1 and when m = 1 the nitrogen is positively charged and the chalcone is a salt;
each of R and R12 is independently selected from the group consisting of -H, -OH, halogens, oxygen, Ci-Ce hydrocarbyl groups, saccharide moieties and -OR18 wherein R« is selected from the group consisting of -H and a Ci to Ce hydrocarbyl group;
each of R13, R14 and R15 is independently selected from the group consisting of -H, -OH, halogens, C1-C6 hydrocarbyl groups, saccharide moieties and -OR18 wherein R 8 is selected from the group consisting of -H and a Ci to Ce hydrocarbyl group so that the nitrogen may be selected from a primary, secondary, tertiary or quaternary amine, an amine oxide and an amine acetate; or
- (Ri3Ri4(Ris)m) are collectively a cyclic amine, including an aromatic amine and also including cyclic amines which include other hetero atoms; and the remainder of each of Ri , R2, R3, R4, Rs, Re, R7, Re. F¾, R10, R16 and Rn, is independently selected from the group consisting of -H, -OH, halogens, CF3, CHF2,CH2F, nitro moieties, amino moieties (but excluding (7-Chloro-4-quinolinyl)amino), sulfonic moieties, sulphanilamide moieties, cyano moieties, sulphide moieties, sulfoxide moieties, sulfone moieties, phosphonate moieties, phosphate moieties, d-
Ce hydrocarbyl moieties, saccharide moieties and -OR13 wherein R-ie is selected from the group consisting of -H, and a Ci to C6 hydrocarbyl group, with the proviso that when R7 and R9 are both dimethylaminomethyl groups and R8 is an
hydroxy group then R3 and R4 shall not both be -H or -CI or R3 shall not be -Br when R4 is -H, and with the further proviso that when R2 and R4 are both dimethylaminomethyl groups and R3
and R8 are both hydroxyl groups then at least one of Ri , R5, R6, R7, R9, R10, Rie and R17 shall not be -H, and analogues and derivatives of a chalcone of Formula 10, and pharmaceutically acceptable salts and solvates of the chalcones, its analogues and derivatives.
In one form of the invention there is provided a compound which is a derivative of a chalcone of the Formula 10 which is selected from the group consisting of compounds represented by the general Formula 25a or general Formula 25b
Formula 25a Formula 25b
wherein the substituents Ri to R17 are as defined above and R25 is selected from the group consisting of -H, -OH, halogens, CF3, CHF2.CH2F, nitro moieties, amino moieties, sulfonic moieties, sulphanilamide moieties, cyano moieties, sulphide moieties, sulfoxide moieties, sulfone moieties, phosphonate moieties, phosphate moieties, Ci- C6 hydrocarbyl moieties, saccharide moieties and -ORi8 wherein Ri8 is selected from the group consisting of -H, and a Ci to Ce hydrocarbyl group.
In another form of the invention there is provided a compound which is a cyclised flavonoid derivative of a chalcone of Formula 10 selected from the group consisting of flavanones of the Formula 3, flavones of the Formula 4, flavonols of the Formula 5, flav-3-enes of the Formula 6, flavan-3-ols of the formula 7, 3-oxo-flavans of the Formula 8 and flavanols of formula 9
Formula 3 Formula 4
wherein the substituents F¾ to Rio are as defined above.
In a further form of the invention there is provided a compound which is an hydrogenated derivative of a compound of Formula 10 in which the alkene group beween the two aromatic rings is hydrogenated to render the compound a dihydrochalcone in which the two aromatic rings are linked by a propanoid moiety with a carbonyl in the 1 -position, the analogue compound having a structure as set out in Formula B1
Formula B 1
wherein the substituents Ri to Rio are as defined above.
Also according to the invention there is provided a compound which is an hydrogenated derivative of a compound of Formula 10 in which the carbonyl group between the two aromatic rings is hydrogenated to reduce the compound to a 1 ,3-diaryl-prop-2-ene in which the two aromatic rings are linked by a propene moiety with a 2,3- double bond, the analogue compound having a structure as set out in Formula B2
wherein the substituents Ri to R10 are as defined above. Again in accordance with the present invention there is provided a compound which is an hydrogenated derivative of a compound of Formula 10 in which both the carbonyl group and alkene groups between the two aromatic rings are hydrogenated to render the compound a 1 ,3-diaryl-propane in which the two aromatic rings are linked by a linear propane moiety, the analogue compound having a structure as set out in Formula B3
Formula B3
wherein the substituents Ri to Rio are as defined above.
Yet further according to the invention there is provided a compound wherein at least one of R6, R7, Re, 9, R10, R16 and R17 in Formula 10 is a hydroxyl group or a derivative of a hydroxy group which hydroxy group or derivative thereof is bound to a carbon adjacent to the carbon on which the alkylamino substituent is bound.
The invention specifically provides for compound designated as bushrachalcone A, having the formula depicted as Formula A
Formula A.
The invention also provides a compound designated as bushrachalcone AB having a structure as set out in formula AB
Formula AB
The invention also provides a compound designated bushrachalcone E having a structure as set out in Formula E
Formula E.
The invention also provides a compound designated bushrachalcone F having a structure as set out in Formula
Formula F
The invention also provides a compound designated bushrachalcone G having a structure as set out in Formula G
Formula H
The invention also provides a compound designated bushrachalcone I having a structure as set out in Formula I
Formula I.
The invention also provides a compound designated bushrachalcone J having a structure as set out in Formula J
Formula J
The invention also provides a compound designated bushrachalcone K having a structure as set out in Formula K
Formula K
The invention also provides a compound designated bushrachalcone L having a structure as set out in Formula
Formula L.
The invention also provides a compound designated bushrachalcone M having a structure as set out in Formula M
Formula .
The invention also provides a compound designated bushrachalcone N having a structure as set out in Formula N
Formula N.
The invention also provides a compound designated bushrachalcone P having a structure as set out in Formula P
Formula P.
The invention also provides a compound designated bushrachalcone R having a structure as set out in Formula R
The invention also provides a compound designated bushrachalcone S having a structure as set out in Formula
Formula S.
The invention also provides a compound designated bushrachalcone T having a structure as set out in Formula T
Formula T
The invention also provides a compound designated bushrachalcone V having a structure as set out in Formula V
Formula V.
The invention also provides a compound designated bushrachalcone W having a structure as set out in Formula W
formula W
Formula W.
The invention also provides a compound designated bushrachalcone W1 having a structure as set out in Formula W1
Formula W1.
The invention also provides a compound designated bushrachalcone X having a structure as set out in Formula X
Formula X
The invention also provides a compound designated bushrachalcone Z having a structure as set out in Formula
Formula Z.
The invention also provides a compound designated bushrachalcone X1 having a structure as set out i Formula X1
Formula X1
The invention also provides a compound designated bushrachalcone X2 having a structure as set out in Formula X2
Formula X2
According to another aspect of the present invention there is provided a method for synthesising a compound according to the invention defined above, including the steps of reacting a suitably substituted chalcone with a suitably selected amine moiety of formula AX in the presence of a non-enolizable aldehyde under acidic or basic Mannich reaction conditions, or alternatively treating a suitably substituted aldehyde with an amine moiety of
formula AX in the presence of a non-enolizable aldehyde under acidic or basic Mannich reaction conditions and converting the resultant compound to a chalcone, and optionally further derivitising the compound,
wherein the amine moiety has a structure of the Formula AX
N( i3 i4 2o(Ri5 Formula AX
in which
m is a numeral which is either 0 or 1 and when m = 1 the nitrogen is positively charged and the amine is a salt;
each of Ri3, Ru. F½ and R20IS independently selected from the group consisting of -H, -OH, halogens, C1-C6 hydrocarbyl groups, saccharide moieties and -OR18 wherein R18 is selected from the group consisting of -H and a Ci to Ce hydrocarbyl group so that the nitrogen may be selected from a primary, secondary, tertiary or quaternary amine, an amine oxide and an amine acetate; or
(Ri3 i4R2o(Ri5)m) are collectively a cyclic amine, including an aromatic amine and also including cyclic amines which include other hetero atoms.
In a preferred for of this aspect of the invention the method as defined above is performed with an amine moiety selected from the group consisting of NH3 or a primary or a secondary amine or cyclic amine or acceptable salt thereof.
Thus the method according to the invention may be performed with NH3, or a primary or secondary amines or cyclic amines which is a hydrochlorides of such compounds.
The invention further provides for a method for synthesising a compound according to the invention as herein defined wherein the non enolizable aldehyde is beforehand reacted with the NH3 or primary or secondary amines or cyclic amines or their suitable salts to form an iminium salt, and such preformed salt is then reacted with the chalcone.
The invention also specifically provides for a method for synthesising bushrachaicone A comprising the steps of preparing a precursor chalcone of Formula B
by performing an aldol condensation between an acetophenone of Formula C and a benzaldehyde of Formula D
Formula Formula D and thereafter treating the chalcone of formula B with formaldehyde in the presence of morpholine to yield buschrachalcone A.
As an alternative the invention provides for a method for synthesising bushrachalcone A comprising the steps of reacting an aminoalkylated acetaldehyde of the structure of Formula D1 with the acetophenone of the structure of Formula C as set out herein under aldol conditions
Formula Dl
Formula D1.
The invention also provides a method for synthesising bushrachalcone E comprising the step of treating bushrachalcone A with methyl iodide.
The invention also provides a method for synthesising bushrachalcone G comprising the step oxidising the benzyl protected form of bushrachalcone A designated bushrachalcone F with hydrogen peroxide or mCPBA to obtain the N-oxide analogue, designated bushrachalcone G as herein defined.
The invention also provides a method for synthesising bushrachalcone I comprising the step of treating bushrachalcone H with acetic acid anhydride in pyridine.
The invention also provides a method for synthesising bushrachalcone K comprising the step of cyclising bushrachalcone J.
The invention also provides a method for synthesising bushrachalcone L comprising the step of deprotecting the hydroxyl group of bushrachalcone J. The invention also provides a method for synthesising bushrachalcone N comprising the step of treating bushrachalcone M with piperidine and formaldehyde.
The invention also provides a method for synthesising bushrachalcone P comprising the step of treating catechin of formula O with dimethylammoniumchloride ((CHs NHCI) in the presence of formaldehyde
Formula O.
The invention also provides a method for synthesising bushrachalcone R comprising the steps of reacting formaldehyde with dimethylamine to form an iminium salt of the formula Q,
formula Q
isolating the iminium salt and reacting the iminium salt with the chalcone of formula B to yield the chalcone analogue designated bushrachalcone R. The invention also provides a method for synthesising bushrachalcone T comprising the step of treating the glycoside of formula S1 with the dimethyl iminium salt of formula Q
Formula S1
The invention also provides a method for synthesising bushrachalcone V comprising the step of aminoalkylating a-hydroxychalcone of formula U
formula U
Formula U
The invention also provides a method for synthesising bushrachalcone X comprising the step of transforming bushrachalcone W via a tosyl intermediate of formula W1 into the trifluoromethyl analogue Bushrachalcone X.
The invention also provides a method for synthesising bushrachalcone Z comprising the step of aminoalkylating compound of formula Y
Formula Y
The invention also provides a method for synthesising bushrachalcone X1 comprising the step of transforming buschrachalcone X with hydroxylamine .
According to a further aspect of the invention it provides for the use of a compound according to the invention as herein defined for the treatment of ailments in animals including man.
The use may thus be for the treatment of cancer or malaria in animals including man.
The invention according to a further aspect thereof also provides for a method for the treatment of ailments in animals including man, and in particular the treatment of cancer or malaria, by administering to an animal in need of such treatment a therapeutically effective dose of a compound according to the invention. Further the invention provides for the use of compounds according to the invention as herein described for use in the manufacture of a medicament for use in the treatment of an ailment in animals including man.
The invention also provides for a pharmaceutical preparation containing a therapeutically effective dose of a compound according to the invention, or part of such dose, in a pharmaceutically acceptable carrier or in combination with one or more pharmaceutically acceptable excipient.
The amine moiety is linked at its nitrogen to the B-ring via a carbon moiety. Flavonoid analogues of bushrachalcone are thus aminoalkylated flavonoids with an aminoalkyl substuent on the B-ring of the flavonoid. The amine moiety of the bushrachaikones and flavonoid analogues can be in the N-H, N-oxide, N-alkyl or N-carbonyl form.
The alkene moiety in the bushrachaikones in chalcone form may be in the Z or E configuration. The alkene is normally unsubsituted but can have substituents such as with a hydroxyl or acetoxy group in which case it is an a- or β- hydroxy- or acetoxychalcone.
In bushrachalcones according to the invention the amine moiety of bushrachalcone may be a primary (NH2), secondary (NHR), tertriary (NR2) or quaternary (NR3 +) amine. In the tertiary and quaternary amines the two or three substituents (R) may be different (e.g. the amine can be R1R2 or RiR2R3+) where Ri , R2 and R3 are different. They may however also be the same. Ri and R2 together with the N to which they are bound can also be part of the same moiety in which case they collectively constitute a cyclic amine e.g. piperidine. Ri , R2 and R3 together with the N to which they are bound may also be aromatic or heterocyclic or both. The nitrogen of the amine group may be oxidised in which case the amine moiety is a nitrogen oxide (N-H replaced by N=0). The nitrogen may also have other substituents e.g. it may be acetylated (N-H replaced by N-OAc) or alkylated (e.g. N- H replaced by CH3).
One or more of the hydroxy groups on the aromatic rings may be replaced by a group that resist enzymatic degradation such as -CF3, a halogen, a C1-C6 alkyl group such as a methyl group or added sugar group such as glucose, in which case it is a C-glycoside of a chalcone.
The presently preferred form the bushrachalcones, herein designated as bushrachalcone A, the amine group is morpholine, and it has the formula depicted as Formula A herein described. Bushrachalcone A has been tested by the applicant and found to have good activity against melanoma and malaria.
In cases where the aromatic ring attached to the alkene group (C3 of the propanoid moiety) has a hydroxyl group in the ortho- position (2"-position) the chalkone may be cyclised via the carbonylgroup on C1 and further transformed with retention or migration of the alkenegroup to yield fiavone derivatives of bushrachalcone. This includes aminoalkylated ftav-3-enes (formula 6) or other aminoalkylated derivatives of chalkones e.g. aminolalkylated flavan-3-ols.
These and other related fiavone derivatives can also be manufactured directly by treating the corresponding flavanone, fiavone or flav-3-ene precursors with an amine in the presence of an aldehyde under acidic or basic annich conditions. The amine may be in the form of hydrochloride or other acid salt form or a preformed iminium salt may be used. Flavan-3-ol and 3-oxo-flavans can be treated in a similar way to obtain flav-3-ol-amines (formula 7) and 3-oxo-flavan (formula 8) derivatives.
In all cases where the aminoalkylated chalcone or other derivatives contain primary, secondary or tertiary amines, the amine moieties may be alkylated to secondary, tertiary and quaternary amines respectively. Primary and secondary amine moieties may also be acetylated to N-acetates or oxidized to amine oxides.
The amine may be any amine, including aliphatic amines such as methylamine, dimethylamine, ethylamine, diethylamine, cyclohexylamine, amphetamine, cyclic amines such as pipendine, pyrrolidine and aromatic amines such as aniline, benzylamine etc.
One or more hydroxy groups of any of the bushrachalcones, chalcone, acetophenone, benzaldehyde or flavones precursor may be protected prior to being coupled to the amine, typically as a benzyl ester or acetate.
The protecting groups may be removed after the synthesis of the bushrachalcones.
EXAMPLES OF THE INVENTION
A. EXAMPLES OF SYNTHESIS OF BUSHRACHALCONES OF THE INVENTION AND STARTING
MATERIALS USED IN SUCH SYNTHESIS.
Without thereby limiting the scope of the present invention it will now be exemplified in the following examples. Generic synthesis:
General reaction procedure for the syntheses of chalcones (£)-3-(3-hydroxyphenyl)-1-(4- methoxyphenyl)-prop-2-en-1-one (a), (E)-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-prop-2-en-1-one (b), (£)-3-(3-hydroxyphenyl)-1-phenylprop-2-en-1-one (c) and (£)-3-(4-hydroxy-3-methoxyphenyl)-1-(4- methoxyphenyl)prop-2-en-1 -one (d).
Structures 1 : Examples of some chalcones used in the syntheses of Bushrachalcones
General Procedure 1. Synthesis of (E)-3-(4-hvdroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (b)
Aldol condensation of 4-hydroxybenzaldehyde with 4-methoxyacetophenone
4-Methoxyacetophenone (3.4793 g; 0.02318 mol) and 4-hydroxybenzaldehyde (3.0055 g; 0.02461 mol) were dissolved in EtOH (50 mL) with constant stirring at room temperature. A 50% KOH solution (50 mL) was added after 10 minutes, which turned the reaction mixture bright yellow. The reaction was left to stir overnight. The reaction mixture was poured over ice and 3 N HCI solution and extracted with EtOAc. The crude mixture was dried over a2S04 and evaporated under reduced pressure. The chalcone product was isolated with column chromatography (cyclohexane:EtOAc 5:5). (£)-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (b) was crystallized from EtOH.
Structure 2: (£)-3-(4-hydroxyphenyl)-1 -(4-methoxyphenyl)prop-2-en-1 -one (b)
Mp: 148-149 °C, v max 1644 cm ~\ [Μ-ΗΓ 253.2, 1H NMR δ (600 MHz, Acet-d6, Me4Si) 3.91 (3H, s, OCH3) 6.92 (2H, d, J = 8.6 Hz, H-3"/H-5"), 7.06 (2H, d, J = 8.6 Hz, H-37H-5'), 7.69 (1 H, d, J = 15.6 Hz, H-2), 7.70 (2H, d, J = 8.6 Hz, H-2"/H-6"), 7.73 (1 H, d, J = 15.6, H-3), 8.14 (2H, d, J = 8.9 Hz, H-27H-6'). 13C NMR δ (150 MHz, Acet-d6, Me4Si) 55.0 (OCH3), 1 13.7 (C-37C-5'), 115.8 (C-3 C-5"), 118.7 (C-2), 126.9 (C-1 "), 130.5 (C-2', C-6'), 130.6 (C- 2 C-6"), 131.4 (C-1 '), 143.4 (C-3), 159.8 (C-4"), 163.4 (C-4'), 187.2 (C-1 ).
General Procedure 2. General reaction procedure for the syntheses of Bushrachalcones.
Mannich reaction of (E)-3-(4-hvdroxyphenyl)-1-(4-methoxyphenv0prop-2-en-1-one b and orpholine (Synthesis of Bushrachalcone).
(£)-3-(4-hydroxyphenyl)-1 -(4-methoxyphenyl)prop-2-en-1-one (b) (486.5 mg; 0.0020mol), paraformaldehyde (59.8 mg; 0.002 mol) and morpholine (0.30 mL; 0.0020 mol) were dissolved in EtOH (2 mL) and cone. HCI (5 drops). The reaction mixture was refluxed for 9 hrs until TLC showed the disappearance of the starting material. The reaction mixture was quenched with NaHCOs and extracted with EtOAc and water. The organic layer was dried over Na2S04 and the solvent evaporated under reduced pressure. Crystallization from EtOH yielded (£ 3-(4- hydroxy-3-(morpholinomethyl)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (A) as yellow crystals.
Structure 3: (£)-3-(4-hydroxy-3-(morpholinomethyl)phenyl)-1-(4-methoxyphenyl)prop-2- en-1-one
Mp: 154-155 °C, [M+H]+ 354.3, I H (600 MHz, Acet-d6, Me4Si): 2.60 (4H, broadend s, H-3"7H-5"') 3.70 (4H, t, J = 4.40 Hz, H-2"7H-6'"), 3.82 (2H, s, CH2), 3.91 (3H, s, OCH3), 6.80 (1 H, d, J = 8.40 Hz, H-5"), 7.06 (2H, d, J = 8.9 Hz, H-37H-5'), 7.58 (1 H, d, J = 2.1 Hz, H-2"), 7.64 (1 H, dd, J = 2.0, 8.4 Hz, H-6"), 7.68 (1 H, d, J = 15.6 Hz, H-2), 7.71 (1 H, d, J = 15.6, H-3), 8.13 (2H, d, J = 8.9 Hz, H-27H-6'). I c (150 MHz, Acet-d6, Me4Si): 52.8 (2 x N-C), 55.1 (OCH3), 60.9 (CH2), 66.4 (2 x O-C), 113.7 (C-37C-5'), 116.2 (C-5"), 1 18.7 (C-2), 121.8 (C-3"), 126.5 (C-1"), 129.7 (C-2", C-6"), 130.6 (C-27C-6'), 131.4 (C-1 '), 143.3 (C-3), 160.4 (C-4"), 163.4 (C-4'), 187.1 (-C=0).
Specific examples:
Group 1. Bushrachalcones of (£)-3-(3-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (a).
Compound (a) was prepared via aldol condensation, as described under general synthesis 1 , of
4methoxyacetophenone and 3-hydroxybenzaldehyde.
EXAMPLE 1
Preparation of (£)-3-(4-((Dimethylamino)methyl)-3-hvdroxyphenyl)-1-(4-methoxyphenvnprop-2-en-1-one
Compound a was reacted with dimethyl amine under Mannich conditions as described under general procedure 2. The procedure yielded the title compound with the following physical data:
Mp: 135-136 °C IR: v max 1651 cm "1 , [M-H]" 310.1 , ! H (600 MHz, CDCI3): 2.36 (s, 6H, 2x -N-CH3), 3.69 (s, 2H, - N-CH2), 3.89 (s, 3H, -OCH3), 6.98 (d, J = 8.8 Hz, 2H, H-2V6'), 7.01 (d, J = 7.6 Hz, 1 H, H-5"), 7.03 (dd, 1 H, J = 7.6 Hz, J = 1.5 Hz, H-6"), 7.15 (d, 1 H, J = 1.5 Hz, H-2"), 7.51 (d, J = 15.6 Hz, 1 H, H-2), 7.73 (d, J = 15.6 Hz, 1 H, H- 3), 8.03 (d, J = 8.8 Hz, 2H, H-375'). I c (150 MHz, CDCI3): 44.4 (2x -N-CH3), 55.4 (-N-CH2-), 62.5 (-OCH3), 1 3.8 (C-3751), 114.8 (C-6"), 120.0 (C-2), 121.0 (C-5"), 124.2 (C-2761), 128.8 (C-2"), 130.0 (C-1 "), 130.7 (C-1 '), 135.8 (C-4"), 143.8 (C-3), 158.4 (C-3"), 163.3 (C-4'), 188.7 (-C=0).
(E)-3-(4-((dimethylamino)methyl)-3-h^ EXAMPLE 2
Preparation of (£)-3-(3-hvdroxy-4-(morpholinomethyl)phenyl¾-1-(4-methoxyphenyl)prop-2-en-1-one
Compound a was reacted with morpholine under Mannich conditions as described under general procedure 2. The procedure yielded the title compound with the following physical data:
Mp: 145-147 °C, \R: vmax 1654 cm"1 , [M+H]+ 354.3, I H (600 MHz, CDCI3): 2.60 (m, 4H, H-2' 6'"), 3.73 (m, 4H, H-3' 5'"), 3.78 (s, 2H, -N-CH2-), 3.90 (s, 3H, -OCH3 ), 6.98 (d, J = 8.8 Hz, 2H, H-276'), 7.04 (d, J = 7.7 Hz, 1 H, H- 5"), 7.15 (dd, J = 7.6 Hz, J = 1.6 Hz, 1 H, H-6"), 7.18 (d, J = 1.6 Hz, 1 H, H-2"), 7.52 (d, J = 15.6 Hz, 1 H, H-2), 7.73 (d, J = 15.6 Hz, 1 H, H-3) 8.03 (d, J = 8.8 Hz, 2H, H-375'). I c (150 MHz, C3D60): 52.9 (C-2"^), 55.4 (-OCH3), 61.4 (C-3'75'"), 66.7 (-N-CH2-), 1 13.8 (C-375'), 1 15.0 (C-6"), 120.4 (C-2), 121 .8. (C-2"), 123.2 (C-4"), 129.3 (C-5"), 130.7 (C-276'), 131.1 (C-1'), 136.0 (C-1 "), 143.6 (C-3), 157.8 (C-3"), 163.4 (C-4'), 188.6 (-C=0)
(ii)-3-(3-hydroxy-4-(morpholinomethyl)phenyl)- 1 -(4-methoxyphenyl)prop-2-en- 1 -one EXAMPLE 3
Preparation of (E)-3-(3-hvdroxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1 -(4-methoxyphenyl)prop-2-en-
1-one Compound a was reacted with W-methylpiperazine under Mannich conditions as described under general procedure 2. The procedure yielded the title compound with the following physical data:
Mp: 136-137 °C, IR: v max 1653.7 cm"1 , ; H (600 MHz, CDCI3): 2.17 (s, 3H, -N-CH3), 2.32 (m, 4H, H-3"75"' ), 2.32 (m, 4H, H-2'76'"), 3.75 (s, 2H, -IM-CH2), 3.89 (s, 3H, -OCH3), 6.98 (d, J = 8.8 Hz, 2H, H-276'), 7.00 (d, J = 7.7 Hz, 1 H, H-5"), 7.13 (dd, J = 7.7 Hz, J = 1.5 Hz, 1 H, H-6"), 7.15 (d, J = 1 .5 Hz, 1 H, H-2"), 7.51 (d, J = 15.6 Hz, 1 H, H-
2), 7.73 (d, J = 15.6 Hz, 1 H, H-3), 8.03 (d, J = 8.8 Hz, 2H, H-375'). ! c ( 50 MHz, CDCI3): 45.8 (-N-CH3), 52.5 (C- 3*75'"), 54.8 (C-2"76m), 55.4 (-OCH3), 61.2 (-N-CH2), 113.8 (C-3751), 114.9 (C-6"), 120.0 (C-2), 121.7. (C-2"), 123.8 (C-4"), 129.1 (C-3), 130.7 (C-276'), 131.1 (C-1 '), 135.8 (C-1 "), 143.8 (C-3"), 158.1 (C-5"), 163.3 (C-4'), 188.7 (-C=0)
(£)-3-(3-hydroxy-4-((4-methylpiperazin- 1 -yl)methyl)pheny I)- 1 -(4-methoxypheny l)prop-2 -en- 1 -one
2. Bushrachalcones of (£)-3-(4-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (b). The synthesis of b is described under general synthesis 1.
EXAMPLE 4
Preparation of (E)-3-(3-(f4-ethylpiperazin-1-yl¾methvH-4-hvdroxyphenyl)-1-(4-methoxy-phenyl)prop-2-en-1- one Compound b was reacted with W-ethylpiperazine under Mannich conditions as described under general procedure 2. The procedure yielded the title compound with the following physical data:
IR: v max 1660 ! H (600 MHz, CDCI3): 1.17 (t, J = 7.3 Hz, 3H, -N-CH2-CH3), 2.59 (q, J = 7.3 Hz, 2H, -N-CH2-CH3) 2.75 (m, 8H, 4x -N-CH2), 3.83 (s, 2H, -CH2), 3.88 (s, 3H, -OCH3), 6.84 (d , J = 8.4. Hz, 1 H, 5"-H), 6.96 (d, J = 8.8 Hz, 2H, 276'-H), 7.30 (d, J 1.6 Hz, 1 H, 2"-H), 7.38 (d, J = 15.4 Hz, 1 H, 2-H), 7.48 (dd, J = 8.4, Hz, J = 1.6 Hz, 1 H, 6"-H), 7.72 (d, J = 15.4 Hz, 1 H, 3-H), 8.03 (d, J = 8.8 Hz, 2H, 375'-H). ί c (150 MHz, CDCI3): 11.3 (-N- CH2CH3), 51.7 (-N-CH2CH3), 52.1 (C-3"75'"), 52.2 (C-2"76'"), 55.4 (-OCH3), 60.9 (-CH2), 113.7 (C-375'), 116.8 (C- 5"), 1 18.9 (C-2), 121.2 (C-3"), 126.6 (C-1 '), 129.1 (C-6"), 129.7 (C-2"), 130.4 (C-276'), 131.1 (C-1 "), 143.9 (C-3), 160.2 (C-4"), 163.2 (C-4'), 188.6 (-C=0)
-((4-ethylpiperazin-l -yl)methyl)-4-hydroxyphenyl)-l-(4- methoxypheny l)prop-2-en- 1 -one
EXAMPLE 5
Preparation of (£)-3-(4-hvdroxy-3.5-bis(piperidin-1-ylmethyl)phenyl)-1 -(4-methoxy- phenyl)prop-2-en-1-one
Compound b was reacted with piperidine under Mannich conditions as described under general procedure 2. The procedure yielded the title compound with the following physical data:
Mp: 192-193 °C. IR: vmax 1649.8 cm "1. : H (600 MHz, C3D60): 1.63 (m, 8H, 2 x H-3'75'"), 1.82 (m, 4H, 2x H-4'") 2.50 (m, 8H, 2 x H-2' 6'"), 3.64 (s, 4H, -N-CH2), 3.90 (s, 3H, -OCH3), 6.98 (d, J = 8.8 Hz, 2H, H-276'), 7.39 (s, 2H, H-276"), 7.40 (d, J = 15.5 Hz, 1 H, H-2), 7.74 (d, J = 15.5 Hz, 1 H, H-3), 8.05 (d, J = 9.0 Hz, 2H, H-3V5'). ! c (150 MHz, CDCI3): 24.0 (2 x C-4'"), 25.7 (2 x C-3"V5'"), 54.1 (2 x C-2'76'"), 55.4 (-OCH3)) 59.3 (-N-CH2), 113.7 (C- 3V5'),118.5 (C-2), 123.3 (C-1 "), 125.4 (C-11), 130.7 (C-276'), 131.5 (C-375"), 144.6 (C-3), 159.4 (C-4"), 163.1 (C- 4'), 188.9 (-C=0)
(£)-3-(4-hydroxy-3,5-bis(piperidin- l-ylmethyl)phenyl)- l-(4-methoxyphenyl)prop-
2-en- l-one
Group 3.Bushrachalcone of (£)-3-(3-Hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (c). (c) was prepared via aldol condensation, as described under general synthesis 1 , of acetophenone and 3- hydroxybenzaldehyde.
EXAMPLE 6
Preparation of (£)-3-(3-hyclroxy-4-(plperidin-1 -ylmethvnphenvH-1-phenylprop-2-en-1-one Compound c was reacted with piperidine under Mannich conditions as described under general procedure 2. The procedure yielded the title compound with the following physical data:
Mp 120-121 °C. IR (KBr): vmax = 2933.9, 1660.32, 1603.07, 1275.16 cm"1 , [M-H]" 320.4, 1 H NMR δ (600 MHz, Acet-de, Me4Si) 8.02 (2H, d, J = 7.9 Hz, H-2', H-6'), 7.76 (1 H, d, J = 15.7 Hz, H-3), 7.60 (1 H, m, H-4'), 7.51 (1 H, d, J = 15.7 Hz, H-2), 7.54-7.50 (2H, m, H-3', H-5'), 7.14 (1 H, d, J = 1.54 Hz, H-2"), 7.05 (1 H, dd, J = 1.5, 7.8 Hz, H- 6"), 7.01 (1 H, d, J = 7.8 Hz, H-5"), 3.72 (2H, s, CH2), 1.96-1 .00 (10H, 5 x N-CH2). 13C NMR δ (150 MHz, Acet-de, Me4Si) 190.7 (C-1 ), 158.5 (C-3"), 145.0 (C-3), 138.3 (C-1 '), 135.4 (C-1 "), 132.8 (C-4'), 129.0 (C-5"), 128.7 (C- 370-5') (this assignment may interchange), 128.5 (C-27C-6')2, 124.7 (C-4"), 121 .7 (C-2), 120.0 (C-6"), 1 14.9 (C- 2"), 62.1 (CHz), 54.1 (C-2"7C-6"'), 25.9 (C-3"7C-5"'), 23.0 (C-4"').
(£)-3-(3-hydroxy-4-(piperidin- 1 -ylmethy l)pheny 1)- 1 -pheny lprop-2-en- 1 -one
Group 4. Bushrachaicone of (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1- one d. (d) was prepared via aldol condensation, as described under general synthesis 1 , of 4- methoxyacetophenone and 4-hydroxy-3-methoxybenzaldehyde.
EXAMPLE 7
Preparation of (Q-3-(4-hydroxy-3-methoxy-5-(piperidin-1-ylmethv^
1-one
Compound d was reacted with piperidine under Mannich conditions as described under general procedure 2. The procedure yielded the title compound with the following physical data:
Mp 149-150 °C, IR (KBr): vmax = 2939.18, 1650.69, 1603.79, 1157.02 cm"1, [M-H]" 380.5, 1H NMR δ (600 MHz, Acet-de, Me4Si) 8.12 (2H, d, J = 8.8 Hz, H-2', H-6'), 7.71 (1H, d, J = 15.5, H-3), 7.68 (1 H, d, J = 15.5 Hz, H-2), 7.38 (1 H, d, J = 1.6 Hz, H-2"), 7.13 (1 H, d, J = 1.6 Hz, H-6"), 7.06 (2H, d, J = 8.8 Hz, H-3', H-5'), 3.91 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.76 (2H, s, CH2), 2.56 (4H, broadend s, H-2'", H-6'"), 1.65 (4H, m, H-3'", H-5'"), 1.53 (2H, broadend s, H-4'"). 13C NMR δ (150 MHz, Acet-d6, Me4Si) 187.3 (C-1 ), 163.3 (C-4'), 151.1 (C-4"), 150.9 (C- 1"), 148.4 (C-3"), 144.0 (C-3), 130.6 (C-27C-6'), 125.9 (C-1 '), 123.0 (C-6"), 122.2 (C-5"), 118.6 (C-2), 113.8 (C- 37C-5'), 111.1 (C-2"), 61.1 (CH2), 55.5 (OCH3), 55.0 (OCH3), 53.5 (C-2"7C-6'"), 25.7 (C-3"7C-5"'), 23.7 (C-4'").
(i?)-3-(4-hydroxy-3-methoxy-5-(piperidin-l-ylmethyl)phenyl)-l-(4- methoxyphenyl)prop-2-en- 1 -one
5. Many variations of the invention may be devised without thereby departing from the scope of the statements of the invention as set out above:
The diarylpropane e [3-(3-hydroxyphenyl)-1-(4-methoxyphenyl)propane] was synthesized via reduction of the carbonyl group and double bond of a using conventional methods (Pd(OH)2/C/H2).
3-(3-hydroxyphenyl)- 1 -(4-methoxyphenyl)propane
EXAMPLE 9
Preparation of 3-(3-hvdroxy-4-(piperidin-1-ylmethyl)phenyl)-1-(4-methoxyphenvi)propane
Compound e was reacted with piperidine under Mannich conditions as described under general procedure 2. The procedure yielded the title compound with the following physical data:
[M+H]+ 340.3, 1H NMR δ (600 MHz, Acet-de, Me4Si) 7.15 (2H, d, J = 8.6 Hz, H-2', H-6'), 6.90 (1 H, d, J = 7.3 Hz, H-5"), 6.87 (2H, d, J = 8.6 Hz, H-3', H-5'), 6.60 (1 H, broadende s, H-2"), 6.58 (1 H, dd, J = 1.6, 7.3 Hz, H-6"), 3.77 (3H, s, OCH3), 3.62 (2H, s, CH2), 2.59 (2H, t, J = 7.6 Hz, H-1 )( This assignment may interchange), 2.55 (2H, t, J = 7.6 Hz, H-3)2, 2.47 (4H, broadend s, H-2'", H-6'"), 1.88 (2H, m, H-2), 1.58 (4H, m, H-3"', H-5'"), 1.48 (2H, broadend s, 1 x H-4'"). 3C NMR δ (150 MHz, Acet-d6, Me4Si) 158.2 (C-4'), 157.9 (C-3"), 142.8 (C-1 "), 134.2 (C- 1 '), 129.2 (C-2VC-6'), 128.4 (C-5"), 1 19.2 (C-4"), 118.7 (C-6"), 1 15.6 (C-2"), 113.6 (C-37C-5'), 61.52 (CH2), 54.5 (2 x N-C), 53.5 (OCH3), 35.0 (C-3), 34.4 (C-1 ), 33.4 (C-2), 25.8 (2 x N-C), 23.9 (1 x N-C).
3-(3-hydroxy-4-(piperidin-l-ylmethyl)phenyl)-l-(4-methoxyphenyl)propane
B. BIOLOGICAL ACTIVITY DETERMINATIONS In this section the results of assays to demonstrate biological activity of some of the compounds according to the invention are reported. Different reference numbers are however used in referring to the compounds, in particular OslbAnke 4 is the bushrachalcone of Formula W
Ojvdwaw 720 is the bushrachalcone of Formula F
Ojvdwaw 723 is the bushrachalcone of Formula A.
1. Antimalaria activity of selected Bushrachalcones and derivatives thereof.
1. Objectives
• To test samples for in vitro antiplasmodial activity against a chloroquine sensitive (CQS) strain of Plasmodium falciparum (D10)
• To test samples for in vitro cytotoxicity against a mammalian cell-line, Chinese Hamster Ovarian (CHO) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT)-assay
Methodology
2.1 Antiplasmodial assay
Continuous in vitro cultures of asexual erythrocyte stages of P. falciparum were maintained using a modified method of Trager and Jensen (1976). Quantitative assessment of antiplasmodial activity in vitro was determined via the parasite lactate dehydrogenase assay using a modified method described by Makler (1993). The test samples were tested in triplicate on one or two separate occasions.
The test samples were prepared to a 20 mg/ml stock solution in 100% DMSO. Stock solutions were stored at -20° C. Further dilutions were prepared in DMSO and complete medium on the day of the experiment. Samples were tested as a suspension if not completely dissolved. Chloroquine (CQ) was used as the reference drug. A full dose-response was performed to determine the concentration inhibiting 50% of parasite
growth (IC50-value). Test samples were initially tested at a starting concentration of 100 pg/MI, which was then serially diluted 2-fold in complete medium to give 10 concentrations, with the lowest concentration being 0.2 pg/ml. The same dilution technique was used for all samples. Active samples were retested at a starting concentration of 10 g/MI or 1000 ng MI. CQ was tested at a starting concentration of 100 ng/ml. The highest concentration of solvent (0.5%) to which the parasites were exposed to had no measurable effect on the parasite viability (data not shown).
2.2 Cytotoxicity assay
The MTT-assay is used as a colorimetric assay for cellular growth and survival, and compares well with other available assays (Mosman et al., 1983 and Rubinstein et al., 1990). The tetrazolium salt MTT was used to measure all growth and chemosensitivity. The test samples were tested in triplicate on one occasion.
2. Objectives
• To test samples for in vitro antiplasmodial activity against a chloroquine sensitive (CQS) strain of Plasmodium falciparum (D10)
• To test samples for in vitro cytotoxicity against a mammalian cell-line, Chinese Hamster Ovarian (CHO) using the 3-(4,5-dimethylthtazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT)-assay
3. Methodology
2.1 Antiplasmodial assay
Continuous in vitro cultures of asexual erythrocyte stages of P. falciparum were maintained using a modified method of Trager and Jensen (1976). Quantitative assessment of antiplasmodial activity in vitro was determined via the parasite lactate dehydrogenase assay using a modified method described by Makler (1993). The test samples were tested in triplicate on one or two separate occasions.
The test samples were prepared to a 20 mg/MI stock solution in 100% DMSO. Stock solutions were stored at -20 °C. Further dilutions were prepared in DMSO and complete medium on the day of the experiment. Samples were tested as a suspension if not completely dissolved. Chloroquine (CQ) was used as the reference drug. A full dose-response was performed to determine the concentration inhibiting 50% of parasite growth (ICso-value). Test samples were initially tested at a starting concentration of 100 pg/MI, which was then serially diluted 2-fold in complete medium to give 10 concentrations, with the lowest concentration being 0.2 pg/MI. The same dilution technique was used for all samples. Active samples were retested at a starting concentration of 10 pg/MI or 1000 ng/ml. CQ was tested at a starting concentration of 100 ng/MI. The highest concentration of solvent (0.5%) to which the parasites were exposed to had no measurable effect on the parasite viability (data not shown).
2.2 Cytotoxicity assay
The MTT-assay is used as a colorimetric assay for cellular growth and survival, and compares well with other available assays (Mosman et al., 1983 and Rubinstein et al., 1990). The tetrazolium salt MTT was used to measure all growth and chemosensitivity. The test samples were tested in triplicate on one occasion.
The sample preparation was the same as for the antiplasmodial testing. Dilutions were prepared on the day of the experiment. Emetine was used as the reference drug in all experiments. The initial concentration of emetine was 100 ug ml, which was serially diluted in complete medium with 10-fold dilutions to give 6 concentrations, the lowest being 0.001 pg/ml. The same dilution technique was applied to all the test samples. The highest concentration of solvent (0.5%) to which the cells were exposed to had no measurable effect on the cell viability (data not shown).
The 50% inhibitory concentration (IC50) values were obtained from full dose-response curves, using a nonlinear dose-response curve fitting analysis via GraphPad Prism v.4 software.
3. Results
The results obtained are represented in Table 1 below and in the attached graphs in which are
Figurel . Dose-response curves of test samples against the CQS D10 strain of P. falciparum and
Figure2. Dose-response curves of test samples against the CHO cell-line.
Table 1. ICso-values of compounds tested in vitro for antiplasmodial activity and cytotoxicity
n=number of data sets averaged
Selectivity index (SI) = IC50 CHO/IC50 D10
4. Discussion
The results showed that Ojvdwaw 720 was the most promising compound with good activity against the CQS strain of the parasite P. falciparum (IC50 = 290 ng/MI) and a SI of 234 (Tablel ). Compounds Ojvdwaw 722, Ojvdwaw 723, OslbAnke4, and OslbAnke 1 showed moderate activity with ICso-values ranging from 1 g/MI to 3 pg/MI. 5. References
Makier T, Ries JM, Williams JA, Bancroft JE, Piper RC, Gibbins BL, Hinrichs DJ, 1993. Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity. The American Society of Tropical Medicine and Hygiene 48, 739-741.
Mosmann T, 1983. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods 65, 55-63.
Rubinstein LV, Shoemaker RH, Paull KD, Simon RM, Tosini S, Skehan P, Scudiero DA, Monks A, Boyd MR, 1990. Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay against a diverse panel of human tumor cell lines. Journal of the National Cancer Institute 82, 1113-8.
Trager W, Jensen JB, 1976. Human malaria parasite in continuous culture. Science 193(4254), 673-5.
2. Cytotocicity against cancer cells of selected Bushrachalcones and derivatives thereof.
1. Assay Background The growth inhibitory effects of the compounds were tested in the 3-cell line panel consisting of TK10 (renal), UACC62 (melanoma) and MCF7 (breast) by Sulforhodamine B (SRB) assay.The SRB assay was developed by Skehan and colleagues to measure drug-induced cytotoxicity and cell proliferation. Its principle is based on the ability of the protein dye sulforhodamine B (Acid Red 52) to bind electrostatically in a pH-dependent manner to protein basic amino acid residues of trichloroacetic acid-fixed cells. Under mild acidic conditions it binds to the fixed cellular protein, while under mild basic conditions it can be extracted from cells and solubilized for measurement. The SRB Assay is performed at CSIR in accordance with the protocol of the Drug Evaluation Branch, NCI, and the assay has been adopted for this screen. MATERIALS AND METHOD
The human cell lines TK10, UACC62 and MCF7 was obtained from NCI in the framework of a collaborative research program between CSIR and NCI. Cell lines was routinely maintained as a monolayer cell culture at 37 °C, 5% CO2, 95% air and 100% relative humidity in RPMI containing 5% fetal bovine serum, 2 mM L-glutamine and 50pg/MI gentamicin.
For the screening experiment, the cells (3-19 passages) were inoculated in 96-well microtiter plates at plating densities of 7-10 000 cells/well and were incubated for 24 h. After 24 h one plate was fixed with TCA to represent a measurement of the cell population for each cell line at the time of drug addition (TO).The other plates with cells were treated with the experimental drugs which were previously dissolved in DMSO and diluted in medium to produce 5 concentrations (6.25-100 ppm). Cells without drug addition served as control. The blank contains complete medium without cells. Etoposide was used as a standard.
The plates were incubated for 48 h after addition of the compounds. Viable cells were fixed to the bottom of each well with cold 50% trichloroacetic acid, washed, dried and dyed by SRB. Unbound dye was removed and protein- bound dye was extracted with 10 mM Tris base for optical density determination at the wavelength 540 nm using a multiwell spectrophotometer.
The optical density of the test well after 48-h period of exposure to the test drug is T, the optical density at time zero is TO, and the control optical density is C. The TGI is the concentration of test drug where 100 x (T-T0)/(C- T0) = 0. The TGI signifies a cytostatic effect.
The results of five dose screening were reported as TGI (total growth inhibition). The biological activities were separated into 4 categories: inactive (TGI >50 ug/MI or TGI >100μΜ), weak activity (15 pg/MI < TGI <50 pg/MI or
30 μΜ < TGI <100 μ , moderate activity (6.25 μ9/ Ι < TGI <15 pg/ml or 10 μ < TGI <30 μΜ and potent activity (TGI <6.25 Mg/MI or TGI <10 μΜ ).
For each tested compound, four response parameters, GI50 (50% growth inhibition and signifies the growth inhibitory power of the test agent), TGI (which is the drug concentration resulting in total growth inhibition and signifies the cytostatic effect of the test agent), LC50 (50% lethal concentration and signifies the cytotoxic effect of the test agent), LC100 (100% lethal concentration and signifies the cytotoxic effect of the test agent), were calculated for each cell
line. Assay prerequisites:
* Z' factor > 0.5
2. Assay conditions Compounds screened: 13
Test compound concentration: 100 - 0.01 μΜ (5 x 10-fold serial dilutions)
Standard (Etoposide) concentration 100 - 0.01 μΜ (5 x 10-fold serial dilutions)
Z' Factor :
3. Results
The results of the assays are represented in the graphs and associated tables attached hereto as Figures 3 to 10.
4. Results Summary
The results may be summarised as follows
5. Conclusions
Criteria
According to our criterion the compounds are considered inactive if parameter TGI for two cell lines is higher than 50 pg/ml or 100 μΜ. Therefore the samples Ojvdwaw 719 and OslbAnke3 can be considered as inactive at the tested concentrations but may well be active at higher concentrations.
The compounds Ojvdwaw 719 and OslbAnke3 demonstrate higher selectivity at the cell line UACC-62.
Again at the tested concentrations Ojvdwaw 713 and Ojvdwaw 722 can be estimated as weakly active, and OslbAnke 1, OslbAnke 4 and Ojvdwaw 723 can be considered as moderately active . The sample Ojvdwaw 720 is active against cell linesTK and potent against cell lines UACC-62 and MCF-7 (values TGI). Many variations of the invention may be devised without thereby departing from the scope of the statements of the invention as set out above
Claims
CLAIMS.
A compound which is selected from the chalcones of the general Formula 10
Formula 10
wherein:
at least one of Re, R7, Re, R9, R10, R16 and R17 is an aminoalkyl substituent of the general Formula AA:
-C(RiiRi2)N(R13Ri4(Ri5)m) Formula AA in which
m is a numeral which is either 0 or 1 and when m = 1 the nitrogen is positively charged and the chalcone is a salt;
each of R and R12 is independently selected from the group consisting of -H, -OH, halogens, oxygen, Ci-C6 hydrocarbyl groups, saccharide moieties and -ORi8 wherein R18 is selected from the group consisting of -H and a Ci to s hydrocarbyl group; each of R13, 14 and R15 is independently selected from the group consisting of -H, - OH, halogens, C-i-Ce hydrocarbyl groups, saccharide moieties and -ORi8 wherein R18 is selected from the group consisting of -H and a Ci to Ce hydrocarbyl group so that the nitrogen may be selected from a primary, secondary, tertiary or quaternary amine, an amine oxide and an amine acetate; or
-IM(Ri3Ri4(Ri5)m) are collectively a cyclic amine, including an aromatic amine and also including cyclic amines which include other hetero atoms; and the remainder of each of R1 f R2> R3, R4, R5, R6, R7, Re, R9, R10, R16 and R17, is independently selected from the group consisting of -H, -OH, halogens, CF3, CHF2,CH2F, nitro moieties, amino moieties (but excluding (7-Chloro-4-quinolinyl)amino), sulfonic moieties, sulphanilamide moieties, cyano moieties, sulphide moieties, sulfoxide moieties, sulfone moieties, phosphonate moieties, phosphate moieties, Ci-Ce hydrocarbyl moieties, saccharide moieties and -ORie wherein R18 is selected from the group consisting of -H, and a Ci to C6 hydrocarbyl group, with the proviso that when R7 and R9 are both dimethylaminomethyl groups and R8 is an hydroxy group then R3 and R4 shall not both be -H or -CI or R3 shall not be -Br when R4 is -H,
and with the further proviso that when 2 and R4 are both dimethylaminornethyl groups and R3 and Re are both hydroxyl groups then at least one of Ri , R5, R6, R7, R9, R10, R16 and R17 shall not be -H, and analogues and derivatives of a chalcone of Formula 10, and pharmaceutically acceptable salts and solvates of the chalcones, its analogues and derivatives.
2. A compound according to claim 1 which is a derivative of a chalcone of the Formula 10 which is selected from the group consisting of compounds represented by the general Formula 25a or general Formula 25b
Formula 25a Formula 25b
wherein the substituents Ri to R17 are as defined in claim 1 and R25 is selected from the group consisting of -H, -OH, halogens, CF3, CHF2,CH2F, nitro moieties, amino moieties, sulfonic moieties, sulphanilamide moieties, cyano moieties, sulphide moieties, sulfoxide moieties, sulfone moieties, phosphonate moieties, phosphate moieties, Ci-Ce hydrocarbyl moieties, saccharide moieties and -ORi8 wherein Ri8 is selected from the group consisting of -H, and a Ci to Ce hydrocarbyl group.
3. A compound according to claim 1 which is a cyclised flavonoid derivative of a chalcone of Formula 10 selected from the group consisting of flavanones of the Formula 3, flavones of the Formula 4, flavonols of the Formula 5, flav-3-enes of the Formula 6, flavan-3-ols of the formula 7, 3-oxo-flavans of the Formula 8 and flavanols of formula 9
Formula 3 Formula 4
wherein the substituents F¾ to Rio are as defined in claim 1.
A compound according to claim 1 which is an hydrogenated derivative of a compound of Formula 10 in which the alkene group beween the two aromatic rings is hydrogenated to render the compound a dihydrochalcone in which the two aromatic rings are linked by a propanoid moiety with a carbonyl in the 1 -position, the analogue compound having a structure as set out in Formula B1
A compound according to claim 1 which is an hydrogenated derivative of a compound of Formula 10 in which the carbonyl group between the two aromatic rings is hydrogenated to reduce the compound to a 1 ,3-diaryl-prop-2-ene in which the two aromatic rings are linked by a propene moiety with a 2,3- double bond, the analogue compoun set out in Formula B2
Formula B2 e
A compound according to claim 1 which is an hydrogenated derivative of a compound of Formula 10 in which both the carbonyl group and alkene groups between the two aromatic rings are hydrogenated to render the compound a 1 ,3-diaryl-propane in which the two aromatic rings are linked by a linear propane moiety, the analogue compound having a structure as set out in Formula B3
A compound according to claim 1 wherein at least one of Re, Re, and R in Formula 10 is a hydroxyl group or a derivative of a hydroxy group which hydroxy group or derivative thereof is bound to a carbon adjacent to the carbon on which the alkylamino substituent is bound.
A compound according to claim 1 designated as bushrachalcone A, having the formula depicted Formula A
Formula A.
A compound according to claim 1 designated as bushrachalcone AB having a structure as set out in formula AB
Formula AB
A compound according to claim 1 designated a bushrachalcone E having a structure as set out ' Formula E
Formula E.
11. A compound according to claim 1 designated bushrachalcone F having a structure as set out in
Formula F
A compound according to claim 1 designated bushrachalcone G having a structure as set out in Formula G
A compound according to claim 1 designated bushrachalcone H having a structure as set out in Formula H
Formula H
A compound according to claim 1 designated bushrachalcone I having a structure as set out in Formula
Formula I.
15. A compound according to claim 1 designated bushrachalcone J having a structure as set out in
Formula J
Formula J
6. A compound according to claim 1 designated bushrachalcone K having a structure as set out in Formula K
Formula K
A compound according to claim 1 designated bushrachalcone L having a structure as set out in Formula L
Formula L.
8. A compound according to claim 1 designated bushrachalcone M having a structure as set out in Formula M
Formula M.
A compound according to claim 1 designated bushrachalcone N having a structure as set out in Formula N
Formula N.
A compound according to claim 1 designated bushrachalcone P having a structure as set out in Formula P
Formula P.
A compound according to claim 1 designated bushrachalcone R having a structure as set out in Formula R
Formula R. 22. A compound according to claim 1 designated bushrachalcone S having a structure as set out in Formula S
Formula S.
A compound according to claim 1 designated bushrachalcone T having a structure as set out in Formula T
Formula T
A compound according to claim 1 designated bushrachalcone V having a structure as set out in Formula V
Formula V.
A compound according to claim 1 designated bushrachalcone W having a structure as set out in Formula W
formula W
Formula W.
26. A compound according to claim 1 designated bushrachalcone W1 having a structure as set out in Formula W1
Formula W1.
A compound according to claim 1 designated bushrachalcone X having a structure as set out in Formula X
Formula X
A compound according to claim 1 designated bushrachalcone Z having a structure as set out in Formula Z
Formula Z.
A compound according to claim 1 designated bushrachalcone X1 having a structure as set out in Formula X1
Formula X1 30. A compound according to claim 1 designated bushrachalcone X2 having a structure as set out in Formula X2
Formula X2
A method for synthesising a compound as defined in claim 1 , including the steps of reacting a suitably substituted chalcone with a suitably selected amine moiety of formula AX in the presence of a non- enolizable aldehyde under acidic or basic Mannich reaction conditions, or alternatively treating a suitably substituted aldehyde with an amine moiety of formula AX in the presence of a non-enolizable aldehyde
under acidic or basic Mannich reaction conditions and converting the resultant compound to a chalcone, and optionally further derivitising the compound,
wherein the amine moiety has a structure of the Formula AX
N( 13 i4R2o(Ri5)m ) Formula AX in which
m is a numeral which is either 0 or land when m = 1 the nitrogen is positively charged and the chalcone is a salt); each of R13, R1 ,Ris and R20 is independently selected from the group consisting of -H, -OH, halogens,
Ci-Ce hydrocarbyl groups, saccharide moieties and -OR-m wherein Ri8 is selected from the group consisting of -H and a Ci to Ce hydrocarbyl group so that the nitrogen may be selected from a primary, secondary, tertiary or quaternary amine, an amine oxide and an amine acetate; or (Ri3 i4 2o( is)m) are collectively a cyclic amine, including an aromatic amine and also including cyclic amines which include other hetero atoms.
A method according to claim 31 wherein the amine moiety is selected from the group consisting of NH3 or a primary or a secondary amine or cyclic amine or acceptable salt thereof. 33. A method according to claim 31 wherein the NH3, or primary or secondary amines or cyclic amines utilised in the synthesis methods are hydrochlorides of such compounds.
A method according to claim 31 for synthesising a compound as defined in claim 1 wherein the non enolizable aldehyde is beforehand reacted with the NH3 or primary or secondary amines or cyclic amines or their suitable salts to form an iminium salt, and such preformed salt is then reacted with the chalcone.
A method according to claim 31 for synthesising bushrachalcone A comprising the steps of preparing precursor chalcone of Formula B
by performing an aldol condensation between an acetophenone of Formula C and a benzaldehyde Formula D
Formula C I'ormula D and thereafter treating the chalcone of formula B with formaldehyde in the presence of morpholine to yield buschrachalcone A.
A method according to claim 31 for synthesising bushrachalcone A comprising the steps of reacting an aminoalkylated acetaldehyde of the structure of Formula D1 with the acetophenone of the structure of Formula C as set out herein under aldol conditions
Formula Dl
Formula D1.
37. A method according to claim 31 for synthesising bushrachalcone E comprising the step of treating bushrachalcone A with methyl iodide.
38. A method according to claim 31 for synthesising bushrachalcone G comprising the step oxidising the benzyl protected form of bushrachalcone A designated bushrachalcone F with hydrogen peroxide or mCPBA to obtain the N-oxide analogue, designated bushrachalcone G as herein defined.
39. A method according to claim 31 for synthesising bushrachalcone I comprising the step of treating bushrachalcone H with acetic acid anhydride in pyridine.
40. A method according to claim 31 for synthesising bushrachalcone K comprising the step of cyclising bushrachalcone J .
41. A method according to claim 31 for synthesising bushrachalcone L comprising the step of deprotecting the hydroxyl group of bushrachalcone J. 42. A method according to claim 31 for synthesising bushrachalcone N comprising the step of treating bushrachalcone M with piperidine and formaldehyde.
43. A method according to claim 31 for synthesising bushrachalcone P comprising the step of treating catechin of formula 0 with dimethylammoniumchloride ((CH3)2NHCI) in the presence of formaldehyde
Formula O.
44. A method according to claim 31 for synthesising bushrachalcone R comprising the steps of reacting formaldehyde with dimethylamine to form an iminium salt of the formula Q,
formula Q
isolating the iminium salt and reacting the iminium salt with the chalcone of formula B to yield the chalcone analogue designated bushrachalcone R. 45. A method according to claim 31 for synthesising bushrachalcone T comprising the step of treating the glycoside of formula S1 with the dimethyl iminium salt of formula Q
aminoalkylating a-hydroxychalcone of formula U
A method according to claim 31 for synthesising bushrachalcone X comprising the step of transforming bushrachalcone W via a tosyl intermediate of formula W1 into the trifluoromethyl analogue Bushrachalcone X.
A method according to claim 31 for synthesising bushrachalcone Z comprising the step of aminoalkylating a compound of formula Y
0 ormu a
49. A method according to claim 31 for synthesising bushrachalcone X1 comprising the step of transforming buschrachalcone X with hydroxylamine .
50. The use of a bushrachalcone as claimed in claim 1 for the treatment of ailments in animals including man.
The use of a bushrachalcone as claimed in claim 49 for the treatment of cancer or malaria in animals including man.
A method for the treatment of ailments in animals including man, and in particular cancer or malaria, by administering to an animal in need of such treatment a therapeutically effective dose of a
bushrachalcone according to claim 1.
The use of bushrachalcones as claimed in claim 1 for use in the manufacture of a medicament for use in the treatment of an ailment in animals including man.
54. A pharmaceutical preparation containing a therapeutically effective dose of a bushrachalcone as claimed in claim 1 , or part of such dose, in a pharmaceutically acceptable carrier or in combination with one or more pharmaceutically acceptable excipient
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775288A (en) * | 2012-07-12 | 2012-11-14 | 温州大学 | Synthetic method of chalcone compounds |
| CN109608346A (en) * | 2019-01-11 | 2019-04-12 | 四川大学 | Chalcone bis-Mannich base compound, its preparation method and use |
| CN109665969A (en) * | 2019-01-11 | 2019-04-23 | 四川大学 | The double Mannich alkaloid compounds of 3- methoxyl group -4-HC, preparation method and use |
| CN109678736A (en) * | 2019-01-11 | 2019-04-26 | 四川大学 | Chalcone Mannich alkaloid compound, preparation method and use |
| CN109734614A (en) * | 2019-01-11 | 2019-05-10 | 四川大学 | 3-Hydroxychalcone Mannich base compound, its preparation method and use |
| CN112694392A (en) * | 2020-12-21 | 2021-04-23 | 青岛大学 | TRPV3 inhibitor and preparation method thereof |
| CN112826812A (en) * | 2020-12-21 | 2021-05-25 | 青岛大学 | A kind of pharmaceutical composition for treating colon cancer and application thereof |
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Non-Patent Citations (4)
| Title |
|---|
| MAKLER MT, RIES JM, WILLIAMS JA, BANCROFT JE, PIPER RC, GIBBINS BL, HINRICHS DJ: "Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity", THE AMERICAN SOCIETY OF TROPICAL MEDICINE AND HYGIENE, vol. 48, 1993, pages 739 - 741 |
| MOSMANN T: "Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays", JOURNAL OF IMMUNOLOGICAL METHODS, vol. 65, 1983, pages 55 - 63, XP023973702, DOI: doi:10.1016/0022-1759(83)90303-4 |
| RUBINSTEIN LV, SHOEMAKER RH, PAULL KD, SIMON RM, TOSINI S, SKEHAN P, SCUDIERO DA, MONKS A, BOYD MR: "Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay against a diverse panel of human tumor cell lines", JOURNAL OF THE NATIONAL CANCER INSTITUTE, vol. 82, 1990, pages 1113 - 8 |
| TRAGER W, JENSEN JB: "Human malaria parasite in continuous culture", SCIENCE, vol. 193, no. 4254, 1976, pages 673 - 5 |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775288A (en) * | 2012-07-12 | 2012-11-14 | 温州大学 | Synthetic method of chalcone compounds |
| CN109608346A (en) * | 2019-01-11 | 2019-04-12 | 四川大学 | Chalcone bis-Mannich base compound, its preparation method and use |
| CN109665969A (en) * | 2019-01-11 | 2019-04-23 | 四川大学 | The double Mannich alkaloid compounds of 3- methoxyl group -4-HC, preparation method and use |
| CN109678736A (en) * | 2019-01-11 | 2019-04-26 | 四川大学 | Chalcone Mannich alkaloid compound, preparation method and use |
| CN109734614A (en) * | 2019-01-11 | 2019-05-10 | 四川大学 | 3-Hydroxychalcone Mannich base compound, its preparation method and use |
| CN109665969B (en) * | 2019-01-11 | 2022-04-22 | 四川大学 | 3-Methoxy-4-hydroxychalcone bis-Mannich base compound, its preparation method and use |
| CN112694392A (en) * | 2020-12-21 | 2021-04-23 | 青岛大学 | TRPV3 inhibitor and preparation method thereof |
| CN112826812A (en) * | 2020-12-21 | 2021-05-25 | 青岛大学 | A kind of pharmaceutical composition for treating colon cancer and application thereof |
| CN112826812B (en) * | 2020-12-21 | 2023-08-25 | 青岛大学 | A kind of pharmaceutical composition and application thereof for treating colon cancer |
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| AP2012006642A0 (en) | 2012-12-31 |
| WO2011151789A3 (en) | 2012-05-24 |
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