CN109369772A - Synthesis method and antitumor application of a kind of phenanthridine derivatives - Google Patents
Synthesis method and antitumor application of a kind of phenanthridine derivatives Download PDFInfo
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- CN109369772A CN109369772A CN201811557248.2A CN201811557248A CN109369772A CN 109369772 A CN109369772 A CN 109369772A CN 201811557248 A CN201811557248 A CN 201811557248A CN 109369772 A CN109369772 A CN 109369772A
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- Prior art keywords
- dimethoxy
- phenanthridine
- tetrahydrobenzo
- phenanthridines
- synthetic method
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- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 13
- 150000005053 phenanthridines Chemical class 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 3
- 229940079593 drug Drugs 0.000 claims abstract 2
- -1 6-(2-dimethylaminoethyl)amino-8,9-dimethoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene pyridine Chemical compound 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 238000010189 synthetic method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 7
- HWFCHCRFQWEFMU-UHFFFAOYSA-N 2-bromo-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(Br)=C(C(O)=O)C=C1OC HWFCHCRFQWEFMU-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- SQMJDLXORYKZGJ-UHFFFAOYSA-N n',n'-bis(methylamino)ethane-1,2-diamine Chemical compound CNN(NC)CCN SQMJDLXORYKZGJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000012320 chlorinating reagent Substances 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- GAENXKVJAIAKQP-UHFFFAOYSA-N 6-chloro-8,9-dimethoxy-1,2,3,4-tetrahydrobenzo[c]phenanthridine Chemical compound ClC=1N=C2C3=C(C=CC2=C2C=C(C(=CC=12)OC)OC)CCCC3 GAENXKVJAIAKQP-UHFFFAOYSA-N 0.000 claims 4
- PHPDEFOCOJSCGM-UHFFFAOYSA-N 8,9-dimethoxy-2,3,4,5-tetrahydro-1h-benzo[c]phenanthridin-6-one Chemical compound C1CCCC2=C(NC(=O)C3=C4C=C(C(=C3)OC)OC)C4=CC=C21 PHPDEFOCOJSCGM-UHFFFAOYSA-N 0.000 claims 4
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical group CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims 2
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 claims 1
- SODWJACROGQSMM-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-1-amine Chemical compound C1CCCC2=C1C=CC=C2N SODWJACROGQSMM-UHFFFAOYSA-N 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 235000015320 potassium carbonate Nutrition 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 36
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 3
- 101150080924 CNE1 gene Proteins 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 229930183010 Amphotericin Natural products 0.000 abstract 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 229940009444 amphotericin Drugs 0.000 abstract 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 abstract 1
- 201000011510 cancer Diseases 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- KKMPSGJPCCJYRV-UHFFFAOYSA-N Nitidine Chemical compound C1=C2C3=[N+](C)C=C4C=C(OC)C(OC)=CC4=C3C=CC2=CC2=C1OCO2 KKMPSGJPCCJYRV-UHFFFAOYSA-N 0.000 description 12
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 125000005605 benzo group Chemical group 0.000 description 6
- 229940049706 benzodiazepine Drugs 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RKAGWJJVDDJVEI-UHFFFAOYSA-N 8,9-dimethoxy-1,2,3,4-tetrahydrobenzo[c]phenanthridine Chemical class C1CCCC2=C1C1=NC=C3C=C(OC)C(OC)=CC3=C1C=C2 RKAGWJJVDDJVEI-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical class CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 3
- BCBUUQWADZNWFN-UHFFFAOYSA-N 1,2,3,4-tetrahydrobenzo[c]phenanthridine Chemical class N1=CC2=CC=CC=C2C(C=C2)=C1C1=C2CCCC1 BCBUUQWADZNWFN-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- VKGXZMNOFKFNLP-UHFFFAOYSA-N CN(C)CCC1=C(C=C(C(OC)=C2)OC)C2=C(C=CC2=C3CCCC2N)C3=N1 Chemical class CN(C)CCC1=C(C=C(C(OC)=C2)OC)C2=C(C=CC2=C3CCCC2N)C3=N1 VKGXZMNOFKFNLP-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 240000003248 Zanthoxylum nitidum Species 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- UWSONZCNXUSTKW-UHFFFAOYSA-N 4,5-Dimethylthiazole Chemical compound CC=1N=CSC=1C UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 1
- 240000008384 Capsicum annuum var. annuum Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000004078 Snake Bites Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- 241000949456 Zanthoxylum Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 210000004881 tumor cell Anatomy 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于有机合成化学技术领域，涉及两面针碱类药物领域，具体而言，提供了一种菲啶类两面针碱衍生物的合成方法及其抗肿瘤应用。实验证明，本发明的菲啶类两面针碱衍生物具有较好的抗肿瘤活性，对HepG2、A549、H460、CNE1癌细胞株都有明显的抑制作用，可用于抗肿瘤药物制备的研究。此外，本发明制备方法反应条件温和，转化率高，底物普适性广。The invention belongs to the technical field of organic synthetic chemistry, and relates to the field of amphotericin drugs. Experiments show that the phenanthridine derivatives of the present invention have good anti-tumor activity, have obvious inhibitory effects on HepG2, A549, H460, CNE1 cancer cell lines, and can be used for the research on the preparation of anti-tumor drugs. In addition, the preparation method of the present invention has mild reaction conditions, high conversion rate and wide substrate universality.
Description
Technical field
Technical field of organic synthesis belonging to the present invention, in particular to a kind of preparation method of phenanthridines class nitidine derivative
And its antitumor application thereof.
Background technique
Radix zanthoxyli (Zanthoxylum nitidum) also known as shinyleaf pricklyash root, climing green pepper, two-sided needle etc. are Rutaceae Zanthoxylum
Liana.The ground such as Guangdong, Guangxi, Fujian are distributed mainly in China.It is wherein the abundantest with the resource in Guangxi, it is Radix zanthoxyli
Genunie medicinal materials producing region.Radix zanthoxyli plant has activating microcirculation and removing stasis medicinal, promoting qi circulation and relieving pain, dispelling wind and removing obstruction in the meridians, removing toxicity for detumescence and other effects.Civil master
It is used to treat traumatic injury, has a stomachache, toothache, rheumatic arthralgia, venomous snake bite, burn and scald etc..
Nitidine (nitidine) mainly extracts from the root of Radix zanthoxyli plant isolated.From structure it be by
Four ring compositions, phenyl ring and phenanthridines ring are connected in parallel, and form the conjugation aromatic rings of planar structure.In recent years, domestic and foreign scholars
It was found that nitidine has good bioactivity, in antitumor, easing pain and diminishing inflammation, anti-malarial, antibacterial, anti HIV-1 virus, painstaking effort
Pipe etc. has remarkable efficacy.Cell activity test shows that it has apparent suppression to liver cancer, lung cancer, breast cancer, nasopharyngeal carcinoma etc.
Effect processed can be induced cell apoptosis by many A signal pathways arresting cell cycle.Due to efficient bioactivity, two sides
Needle alkali is increasingly becoming the important lead compound of developing new drug.Nitidine compound poorly water-soluble itself, bioavailability are low,
Extensive formation efficiency is low, at high cost, is unfavorable for research needs and clinical use, limits its further development.Therefore, right
Its emphasis being transformed into for focus concerned by people and research for carrying out chemical structure.In the present invention, it is desirable to by two sides
Needle alkali carries out structure of modification to overcome these defects, improves the druggability of derivative, reduces poison while improving anti-tumor activity
Property.N-5, C-6 are important and can modify key mapping on nitidine B ring, can be on the basis for retaining nitidine special groups
On, simplify its parent nucleus, design synthesizes the analog that some structures simplify, to obtain a series of with antitumor, anti-inflammatory, anti-
Bacterium, AntiHIV1 RT activity isoreactivity derivative.
Summary of the invention
The purpose of the present invention is to provide the synthetic methods of a kind of novel phenanthridines class nitidine derivative and its antitumor
Using.
The technical scheme of the present invention is realized as follows:
A kind of phenanthridines class nitidine derivative 6- (2- dimethylaminoethyl) amino -8,9- dimethoxy -1,2,3,4-
Tetrahydro benzo [c] phenanthridines (6), structural formula is as follows:
The present invention provides phenanthridines class nitidine derivative 6- (2- dimethylaminoethyl) amino -8,9- as described above
Dimethoxy -1,2, the synthetic method of 3,4- tetrahydro benzos [c] phenanthridines (6), comprising the following steps:
1) using 2-BROMO-4,5-DIMETHOXYBENZOIC ACID as starting material, and 5,6,7,8- tetrahydros-naphthalidine is in organic solvent
Middle reaction obtains the bromo- 4,5- dimethoxy-N- of 2- (5,6,7,8- naphthane -1- base) benzamide (1)；
2) the bromo- 4,5- dimethoxy-N- of 2- (5,6,7,8- naphthane -1- base) benzamide (1) draws in organic solvent
Enter protecting group and obtains compound (2)；
3) coupling reaction occurs in organic solvent for compound (2), obtains key intermediate 8,9- dimethoxy -5- (4-
Methoxy-benzyl) -1,2,3,4- tetrahydro benzo [c] phenanthridines -6- ketone (3)；
4) key intermediate 8,9- dimethoxy -5- (4- methoxy-benzyl) -1,2,3,4- tetrahydro benzo [c] phenanthridines -6-
Ketone (3) is deprotected in acid condition obtains product 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines -6 (5H) -one
(4)；
5) 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines -6 (5H) -one (4) is sent out under the action of chlorinating agent
Raw chlorination obtains chloro- 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines (5) of product 6-；
6) chloro- 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines (5) the generation substitution reaction of 6- obtains target production
Object 6- (2- dimethylaminoethyl) amino -8,9- dimethoxy -1,2,3,4- tetrahydro benzos [c] phenanthridines (6), synthetic route is seen below
It is shown:
In said synthesis route, organic solvent can according to the demand of reaction, from n,N-Dimethylformamide (abbreviation:
DMF), chosen in methylene chloride.Reaction temperature can suitably be chosen according to reaction type.Reaction time can be by monitoring reaction raw materials
Situation obtains.
Dimethoxy -1,2,3 nitidine derivative 6- (2- dimethylaminoethyl) amino -8,9- of the present invention,
The synthetic method of 4- tetrahydro benzo [c] phenanthridines, specifically includes the following steps:
1) 2-BROMO-4,5-DIMETHOXYBENZOIC ACID is taken to be reacted in thionyl chloride, reactant vacuum distillation removes molten
Agent obtains intermediate acid chloride, 5 is added after acyl chlorides is dissolved with methylene chloride, 6,7,8- tetrahydros-naphthalidine, nucleo philic substitution reaction obtains
To 1 amide of intermediate.
2) it takes amide 1 to be dissolved in n,N-Dimethylformamide, sodium hydride is added and is reacted, 4- methoxybenzyl is added
Chlorine, products therefrom obtain intermediate 2 through silica gel column chromatography.
3) it takes intermediate 2 to be dissolved in n,N-Dimethylformamide, palladium acetate, three (o-tolyl) phosphines, potassium carbonate is added and exists
It is reacted under inert gas atmosphere protective condition, products therefrom obtains intermediate 3 through silica gel column chromatography.
4) intermediate 3 is taken, trifluoroacetic acid reaction is added, products therefrom obtains compound 4 through silica gel column chromatography.
5) compound 4 is taken, phosphorus oxychloride reaction is added, products therefrom filters to obtain compound 5 through ice water, concentrated ammonia liquor processing.
6) compound 5 is taken, N, N- dimethylamino ethylenediamine is added, reactant vacuum distillation removes solvent, obtained solid object
Matter is washed, obtains target product 6.
In above-mentioned synthetic reaction step 1), the reaction temperature of 2-BROMO-4,5-DIMETHOXYBENZOIC ACID and thionyl chloride is preferred
It 65 DEG C, reacts preferably using being heated to reflux by the way of, preferably 0 DEG C of nucleophilic substitution temperature to carrying out under room temperature, reaction
Whether thin-layer chromatography tracking and monitoring can be used completely, under the above conditions, reaction to taking around 3h completely.It passes through after reaction
Extraction, concentration, post separation obtain amide 1.The bromo- 4,5- dimethoxybenzoic acid of 2- and 5,6,7,8- tetrahydro -1- naphthalene in the step
Amine molar ratio is preferably 1:1.1, to avoid reaction that acyl chlorides acutely is added portionwise.Silica gel column chromatography in obtained material in the step
When, preferably with the mixed solvent eluent being made of the petroleum ether and ethyl acetate of volume ratio 2:1 to get to centre
Body amide 1.
In above-mentioned synthetic reaction step 2), the molar ratio of amide 1, sodium hydride and 4- methoxyl group benzyl chloride is preferably 1:2:3；On
Stating reaction preferable temperature is to carry out under room temperature, and whether reaction can be used thin-layer chromatography tracking and monitoring completely, in above-mentioned condition
Under, reaction to taking around 8h completely.In the step in obtained material when silica gel column chromatography, preferably with by volume ratio 2:1
Petroleum ether and ethyl acetate composition mixed solvent eluent to get arrive intermediate 2.
In above-mentioned synthetic reaction step 3), intermediate 2, palladium acetate, the molar ratio of three (o-tolyl) phosphines and potassium carbonate are excellent
It is selected as 1:0.1:0.2:4；Above-mentioned reaction preferably carries out at 100 DEG C, and atmospheric condition is preferably nitrogen, and reaction, which preferably uses, to be added
The mode of heat reflux carries out.Under the above conditions, reaction to taking around 10h completely.Silicagel column in obtained material in the step
When chromatography, preferably with the mixed solvent eluent being made of the petroleum ether and ethyl acetate of volume ratio 2:1 to get to
Intermediate 3.
In above-mentioned synthetic reaction step 4), reaction is preferably carried out at 75 DEG C.
In above-mentioned synthetic reaction step 5), react preferred temperature be 105 DEG C (reaction whether thin-layer chromatography can be used completely
Tracking and monitoring), the reaction time is preferably 2h.
In above-mentioned synthetic reaction step 6), the molar ratio of compound 5 and N, N- dimethylamino ethylenediamine are preferably 1:0.04；
Reacting preferred temperature is 104~105 DEG C, and the reaction time is preferably 5h, and atmospheric condition is preferably nitrogen, and reaction, which preferably uses, to be added
The mode of heat reflux carries out.
Active testing proves that the phenanthridines class nitidine derivative as shown in Equation 6 that the present invention designs synthesis has fine
Antitumor action.
Therefore, the present invention provides phenanthridines class nitidine derivatives as shown in Equation 6 to be used to prepare anti-tumor drug
Purposes.Testing through cell activity proves that the derivative has good antitumous effect, it is expected to be used as antineoplastic for clinical
Object.In addition, preparation method reaction condition of the invention is mild, raw material is easy to get, low in cost, high income, easily operated implementation.
Detailed description of the invention
Fig. 1 is 8,9- dimethoxy -5- (4- methoxy-benzyl) -1,2,3,4- tetrahydro benzene prepared by the embodiment of the present invention 1
And [c] phenanthridines -6- ketone1H-NMR figure；
Fig. 2 is 8,9- dimethoxy -5- (4- methoxy-benzyl) -1,2,3,4- tetrahydro benzene prepared by the embodiment of the present invention 1
And [c] phenanthridines -6- ketone13C-NMR figure；
Fig. 3 is 8,9- dimethoxy -5- (4- methoxy-benzyl) -1,2,3,4- tetrahydro benzene prepared by the embodiment of the present invention 1
And the ESI-MS figure of [c] phenanthridines -6- ketone；
Fig. 4 is 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines -6 (5H) -one prepared by the embodiment of the present invention 2
's1H-NMR figure；
Fig. 5 is 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines -6 (5H) -one prepared by the embodiment of the present invention 2
's13C-NMR figure；
Fig. 6 is 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines -6 (5H) -one prepared by the embodiment of the present invention 2
ESI-MS figure；
Fig. 7 is chloro- 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines of 6- prepared by the embodiment of the present invention 31H-NMR figure；
Fig. 8 is chloro- 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines of 6- prepared by the embodiment of the present invention 313C-NMR figure；
Fig. 9 is chloro- 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines of 6- prepared by the embodiment of the present invention 3
ESI-MS figure；
Figure 10 is 6- (2- dimethylaminoethyl) amino -8,9- dimethoxy -1,2,3,4- prepared by the embodiment of the present invention 4
Tetrahydro benzo [c] phenanthridines1H-NMR figure；
Figure 11 is 6- (2- dimethylaminoethyl) amino -8,9- dimethoxy -1,2,3,4- prepared by the embodiment of the present invention 4
Tetrahydro benzo [c] phenanthridines13C-NMR figure；
Figure 12 is 6- (2- dimethylaminoethyl) amino -8,9- dimethoxy -1,2,3,4- prepared by the embodiment of the present invention 4
The ESI-MS of tetrahydro benzo [c] phenanthridines schemes.
Specific embodiment
The present invention is further illustrated below with reference to specific example and biological activity test result, but is not intended to limit this
Invention.
Embodiment 1.8,9- dimethoxy -5- (4- methoxy-benzyl) -1,2,3,4- tetrahydro benzo [c] phenanthridines -6- ketone (3)
Preparation
1) preparation of intermediate (1)
15mL thionyl chloride is added in 2-BROMO-4,5-DIMETHOXYBENZOIC ACID (1.50g, 5.74mmol), at 65 DEG C
It is heated to reflux 1h, revolving removes solvent, obtains white solid acyl chlorides.M-Anisidine (0.930g, 6.32mmol) is dissolved in 3mL
In methylene chloride, 7mL n,N-diisopropylethylamine and the acyl chlorides being dissolved in methylene chloride is added (in 10min to it at 0 DEG C
Inside it is added three times), it transfers to after reacting 1h and stirs 1h at room temperature.After reaction, 1M hydrochloric acid, methylene chloride is added
Extraction, organic phase saturated sodium bicarbonate, saturated salt solution wash respectively, after anhydrous sodium sulfate is dry, are concentrated under reduced pressure, post separation
Obtain white solid, as 2- bromo-4,5-dimethoxy-N- (5,6,7,8- naphthane -1- base) benzamide (1), yield
88.7%, Rf value Rf: 0.45 (solvent is petroleum ether: ethyl acetate=2:1).
2) preparation of intermediate (2)
1mmol intermediate (1) is dissolved in the dry n,N-Dimethylformamide of 10mL, the sodium hydride of 2 times of amounts, room is added
Temperature is lower to stir 30min, is slowly added to the 4- methoxyl group benzyl chloride of 3 times of amounts, continues to be slowly stirred 8h.After reaction, water quenching is added to go out,
Ethyl acetate extraction, organic phase is concentrated under reduced pressure after using water, saturated common salt water washing, anhydrous sodium sulfate dry after merging, with petroleum
The mixed liquor of ether and ethyl acetate is that eluant, eluent carries out column chromatography for separation, obtains intermediate (2), yield 93.2%.
3) preparation of 8,9- dimethoxy -5- (4- methoxy-benzyl) -1,2,3,4- tetrahydro benzo [c] phenanthridines -6- ketone (3)
Intermediate (2) (1.400g, 2.74mmol) is dissolved in the dry n,N-Dimethylformamide of 15mL, vinegar is added
Sour palladium (0.062g, 0.27mmol), three (o-tolyl) phosphines (0.167g, 0.5mmol) and potassium carbonate (1.513g,
10.97mmol), under nitrogen protection, 100 DEG C are heated to reflux 10h.It is cooled to room temperature after reaction, water quenching is added to go out, methylene chloride
Extraction, organic phase water, saturated common salt washing, after anhydrous sodium sulfate is dry, with washing for petroleum ether and ethyl acetate volume ratio 2:1
De- agent carries out post separation, obtains white solid, as 8,9- dimethoxy -5- (4- methoxy-benzyl) -1,2,3,4- tetrahydro benzos
[c] phenanthridines -6- ketone (3), yield: 85.3%.M.p.142.8~144.8 DEG C；IR(KBr,cm-1):3437,3136,1639,
1601,1513,1457,1400,1302,1243,1175,1129,1022,779；1H-NMR(500MHz,CDCl3)δ7.89(d,J
=8.2Hz, 1H), 7.85 (s, 1H), 7.54 (s, 1H), 7.06 (d, J=8.2Hz, 1H), 6.98 (d, J=8.6Hz, 2H),
6.75 (d, J=8.6Hz, 2H), 5.47 (s, 2H), 4.08 (s, 3H), 4.00 (s, 3H), 3.79 (d, J=8.2Hz, 2H), 3.73
(s, 3H), 3.60 (s, 1H), 2.90 (t, J=6.9Hz, 2H), 2.84 (t, J=5.9Hz, 2H), 2.49 (s, 1H)；13C-NMR
(126MHz,CDCl3)δ164.84,158.27,153.59,149.49,139.36,139.21,131.05,130.86,
129.31,128.64,127.44,125.87,124.84,122.74,119.90,113.88,113.68,109.19,102.77,
56.26,56.22,55.30,52.91,30.38,29.71,23.28,22.11.ESI-MS m/z:430.91([M+H]+)。
The preparation of embodiment 2.8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines -6 (5H) -one (4)
Compound (3) (0.640g, 1.49mmol) is taken, the trifluoroacetic acid of 2mL is added, is heated to reflux 10h at 75 DEG C.Reaction
After be cooled to room temperature, add ethyl acetate, water quenching to go out, ethyl acetate extraction, organic phase washing, saturated sodium bicarbonate wash, nothing
After aqueous sodium persulfate is dry, post separation is carried out with the eluant, eluent of methylene chloride and ethyl acetate volume ratio 10:1, obtains white solid, i.e.,
For 8,9- dimethoxy -1,2,3,4- tetrahydro benzos [c] phenanthridines -6 (5H) -one (4), yield: 75.6%.M.p.253.0~
255.0℃；IR(KBr,cm-1):3439,3132,1651,1610,1496,1398,1234,1129,1079,836；1H-NMR
(500MHz,CDCl3) δ 8.56 (s, 1H), 7.87 (d, J=7.4Hz, 2H), 7.59 (s, 1H), 7.03 (d, J=8.3Hz, 1H),
4.10 (s, 3H), 4.04 (s, 3H), 2.88 (t, J=6.1Hz, 2H), 2.77 (t, J=6.4Hz, 2H), 2.51-2.47 (m,
1H),2.01-1.94(m,2H),1.88-1.81(m,2H)；13C-NMR(126MHz,CDCl3)δ153.79,149.51,
138.32,123.84,121.76,119.57,115.92,108.37,102.98,56.25,56.16,29.96,23.44,
22.67,22.40；ESI-MS m/z:310.15([M+H]+)。
The preparation of chloro- 8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines (5) of embodiment 3.6-
It takes compound (4) (0.02mmol) to be placed in a reaction flask, the phosphorus oxychloride of 40mL is added, is heated to reflux at 105 DEG C
2h.It is cooled to room temperature, is carefully poured into the beaker equipped with ice water after reaction, concentrated ammonia liquor is added dropwise to pH in alkalinity, mistake
Filter precipitating, filter cake are washed with water repeatedly, carry out post separation with the eluant, eluent of petroleum ether and methylene chloride volume ratio 1:1, obtain white solid
Chloro- 8, the 9- dimethoxy -1,2 of body, as 6-, 3,4- tetrahydro benzos [c] phenanthridines (5), yield: 84.8%.M.p.201.3~
202.3℃；IR(KBr,cm-1):3434,3133,2928,1613,1578,1523,1501,1465,1402,1299,1249,
1206,1160,1081,1043,953,840；1H-NMR(500MHz,CDCl3) δ 8.13 (d, J=8.4Hz, 1H), 7.83 (s,
1H), 7.72 (s, 1H), 7.35 (d, J=8.5Hz, 1H), 4.14 (s, 3H), 4.09 (s, 3H), 3.35 (t, J=6.1Hz, 2H),
2.96 (t, J=6.0Hz, 2H), 1.93 (ddd, J=17.9,10.9,5.6Hz, 4H), 1.25 (s, 2H)；13C-NMR(126MHz,
CDCl3)δ153.11,149.79,148.43,141.77,137.49,135.21,130.77,128.59,121.41,119.46,
118.50,106.78,102.04,56.20,56.14,30.07,25.23,22.98,22.95；ESI-MS m/z:328.11([M
+H]+)。
Embodiment 4.6- (2- dimethylaminoethyl) amino -8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines
(6) preparation
Compound (5) (5mmol) and N, N- dimethylamino ethylenediamine (0.2mmol) are mixed, under nitrogen protection, 104
~106 DEG C are heated to reflux 5h, are down to room temperature after reaction, and revolving removes solvent, and add methylene chloride dissolution, and organic phase is with 5%
Sodium hydrate aqueous solution washs 2 times, is washed with water, and obtains solid crude product after anhydrous sodium sulfate is dry, and solid crude product is with two
The eluant, eluent of chloromethanes and methanol volume ratio 10:1 carry out post separation, obtain yellow solid, as 6- (2- dimethylaminoethyl) ammonia
Base -8,9- dimethoxy -1,2,3,4- tetrahydro benzos [c] phenanthridines (6), yield: 78.0%.M.p.121.6~123.0 DEG C；IR
(KBr,cm-1):3430,3134,2926,1593,1530,1488,1401,1262,1253,1207,1037,837,784；1H-
NMR(500MHz,CDCl3) δ 7.98 (d, J=8.3Hz, 1H), 7.77 (s, 1H), 7.42 (s, 1H), 7.06 (d, J=8.3Hz,
1H), 4.08 (d, J=4.4Hz, 6H), 3.88 (t, J=5.6Hz, 2H), 3.21 (t, J=6.2Hz, 2H), 2.91 (t, J=
6.1Hz,2H),2.88-2.81(m,3H),2.42(s,6H),1.25(s,2H)；13C-NMR(126MHz,CDCl3)δ152.25,
152.19,149.40,142.09,137.09,132.72,130.04,124.12,118.72,118.16,113.34,104.03,
103.24,58.99,56.80,56.28,45.62,39.47,30.54,25.64,23.82,23.61；ESI-MS m/z:
380.22([M+H]+)。
The anti-tumor activity of 5. phenanthridines class nitidine derivative of embodiment is tested
Phenanthridines class nitidine derivative prepared by 1~embodiment of embodiment 4 is subjected in vitro antitumor activity assay.
Select cell strain: hepatocellular carcinoma H22, lung cell A549 and H460, nasopharyngeal carcinoma cell CNE1.
Experimental method: derivative is diluted to the concentration of required solution with dmso solution.Logarithmic growth phase is thin
Born of the same parents are digested with pancreatin, are made 4 × 104~5 × 104A mL-1Cell suspension is uniformly inoculated in 96 well culture plates, every hole
100 μ L add 100 μ L PBS in the 96 every holes of orifice plate surrounding, are placed in CO to prevent edge effect2After being cultivated for 24 hours in incubator,
It is added by test solution, every 10 μ L of hole, cultivates 48h.By 3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide (MTT)
It is added in 96 orifice plates, every 10 μ L of hole, reacts 4h in incubator.It discards supernatant liquid, is added dimethyl sulfoxide, 100 μ L of every hole is micro
5min is vibrated on oscillator, measures the absorbance in every hole at 570nm with microplate reader, calculates the inhibiting rate of cell.
Cell inhibitory rate (Inhibitory rate, 100%)=(medicine group OD- blank group OD)/(control group OD- blank
Group OD) × 100%
The experimental results are shown inthe following table.
Experimental data shows that phenanthridines class nitidine derivative of the present invention has stronger effect to tumor cell proliferation,
Especially 8,9- dimethoxy -5- (4- methoxy-benzyl) -1,2,3,4- tetrahydro benzo [c] phenanthridines -6- ketone (3) and 6- (2- bis-
Methylaminoethyl) amino -8,9- dimethoxy -1,2,3,4- tetrahydro benzo [c] phenanthridines (6) have efficient anti-tumor activity.
Therefore, the drug candidate of preparation anticancer can be used for.
Claims (8)
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