CN115677580B - A class of tetrahydroquinoline spiroalkaloids containing quaternary carbon indandione and its preparation method and application in the preparation of anti-tumor drugs - Google Patents
A class of tetrahydroquinoline spiroalkaloids containing quaternary carbon indandione and its preparation method and application in the preparation of anti-tumor drugs Download PDFInfo
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- -1 carbon indandione Chemical group 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 title abstract description 5
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- UHKAJLSKXBADFT-UHFFFAOYSA-N 1,3-indandione Chemical compound C1=CC=C2C(=O)CC(=O)C2=C1 UHKAJLSKXBADFT-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 6
- 230000035755 proliferation Effects 0.000 claims abstract description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims abstract 3
- 238000006243 chemical reaction Methods 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001308 synthesis method Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- DMOLTNKQLUAXPI-QHCPKHFHSA-N [2-[(4r)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl]-diphenylphosphane Chemical compound CC(C)(C)[C@@H]1COC(C=2C(=CC=CC=2)P(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 DMOLTNKQLUAXPI-QHCPKHFHSA-N 0.000 claims 2
- 239000012046 mixed solvent Substances 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 102
- 210000004027 cell Anatomy 0.000 description 29
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 239000007787 solid Substances 0.000 description 26
- JVTRZJXFAOQMRA-UHFFFAOYSA-N 1,3-oxazin-2-one Chemical compound O=C1N=CC=CO1 JVTRZJXFAOQMRA-UHFFFAOYSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 238000001228 spectrum Methods 0.000 description 13
- 229910052799 carbon Inorganic materials 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
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- 230000010261 cell growth Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 2
- KRIWIRSMQRQYJG-DLBZAZTESA-N (2s,3s)-3-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]butane-1,2,4-triol Chemical compound C=1C(N[C@@H](CO)[C@H](O)CO)=NC2=C(C(C)C)C=NN2C=1NCC1=CC=CC=C1 KRIWIRSMQRQYJG-DLBZAZTESA-N 0.000 description 1
- LPNRUMVKXCLEBE-JXVRESAISA-L (3r)-4-[[(e)-2-[5-ethyl-4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethenyl]-oxidophosphoryl]-3-hydroxybutanoate Chemical compound CCC1=C(C=2C=CC=CC=2)N=C(C(C)C)C(\C=C\P([O-])(=O)C[C@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 LPNRUMVKXCLEBE-JXVRESAISA-L 0.000 description 1
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 1
- QVBVQHTXLPNXEY-ZMFCMNQTSA-N (4r)-6-[2-[4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 QVBVQHTXLPNXEY-ZMFCMNQTSA-N 0.000 description 1
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
- AKBHYCHPWZPGAH-UHFFFAOYSA-N 2-[3-[(3-chloro-4-methylphenyl)methoxy]azetidine-1-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one Chemical compound CC1=C(Cl)C=C(COC2CN(C2)C(=O)C2CC3(C2)COC(=O)N3)C=C1 AKBHYCHPWZPGAH-UHFFFAOYSA-N 0.000 description 1
- LIDUGWDLSDKCLM-CSKARUKUSA-N 4-[[3-[[[(e)-6,6-dimethylhept-2-en-4-ynyl]-ethylamino]methyl]phenoxy]methyl-dimethylsilyl]benzonitrile Chemical compound CC(C)(C)C#C/C=C/CN(CC)CC1=CC=CC(OC[Si](C)(C)C=2C=CC(=CC=2)C#N)=C1 LIDUGWDLSDKCLM-CSKARUKUSA-N 0.000 description 1
- VVTYQAQSTWKCBY-UHFFFAOYSA-N CC=1S(C=CN=1)(C)(C)C Chemical compound CC=1S(C=CN=1)(C)(C)C VVTYQAQSTWKCBY-UHFFFAOYSA-N 0.000 description 1
- 229940126559 Compound 4e Drugs 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
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- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 230000003833 cell viability Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- CDVMXMZPDJHSCC-UHFFFAOYSA-N chembl1684662 Chemical compound C=1C=C2C=C(C=3C4=NC=CC=C4NN=3)NC2=CC=1CC(=O)C1=CC=CC=C1 CDVMXMZPDJHSCC-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
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- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- DTPIICGKNYGUFI-UHFFFAOYSA-N perophoramidine Natural products C=1C(Br)=CC=C2C=1NC1=NC(C(=CC(Cl)=C3)Cl)=C3C31CCN=C1C32CCN1C DTPIICGKNYGUFI-UHFFFAOYSA-N 0.000 description 1
- DTPIICGKNYGUFI-VQCQRNETSA-N perophoramidine Chemical compound C=1C(Br)=CC=C2C=1NC1=NC(C(=CC(Cl)=C3)Cl)=C3[C@@]31CCN=C1C32CCN1C DTPIICGKNYGUFI-VQCQRNETSA-N 0.000 description 1
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- 150000003248 quinolines Chemical class 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于化学合成技术领域，具体公开了一类含季碳茚满二酮四氢喹啉螺环生物碱及其制备方法和在制备抗肿瘤药物中的应用。以1‑(苯磺酰基)‑4‑乙烯基‑1,4‑二氢‑2H‑苯并[d][1,3]恶嗪‑2‑酮和1,3‑茚二酮为原料，以Pd2(dba)3·CHCl3为催化剂，以(R)‑4‑(叔丁基)‑2‑(2‑(二苯基膦)苯基)‑4,5‑二氢恶唑或BINAP为配体，在氮气保护下，于反应溶剂中，室温反应2~36小时，得到目标化合物。本发明的方法操作简单、收率高。本发明的化合物对肿瘤细胞A549、HELA、MDA‑MB‑231增殖具有显著的抑制活性，可用于制备防治肿瘤疾病的药物。The present invention belongs to the field of chemical synthesis technology, and specifically discloses a class of quaternary carbon indandione tetrahydroquinoline spiro alkaloids and their preparation methods and applications in the preparation of antitumor drugs. 1-(phenylsulfonyl)-4-vinyl-1,4-dihydro-2H-benzo[d][1,3]oxazine-2-one and 1,3-indanedione are used as raw materials, Pd 2 (dba) 3 ·CHCl 3 is used as a catalyst, (R)-4-(tert-butyl)-2-(2-(diphenylphosphine)phenyl)-4,5-dihydrooxazole or BINAP is used as a ligand, under nitrogen protection, in a reaction solvent, react at room temperature for 2 to 36 hours to obtain a target compound. The method of the present invention is simple to operate and has a high yield. The compound of the present invention has significant inhibitory activity on the proliferation of tumor cells A549, HELA, and MDA-MB-231, and can be used to prepare drugs for preventing and treating tumor diseases.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and in particular relates to quaternary carbon indandione tetrahydroquinoline spiro alkaloids shown in a formula (I), a synthesis method and pharmaceutical application thereof.
Background
Tetrahydroquinoline and quinoline structural units are widely used as an important heterocyclic skeleton structural unit in many natural products, clinical medicines, pesticides and other bioactive compounds, and often show various excellent bioactivity. For example, natural products Communesin family and Perophoramidine each have tetrahydroquinoline building blocks. The quinolinone antibacterial drugs such as levofloxacin (Levaquin) and ciprofloxacin (Ciprofloxacin) are widely applied in medicine. In addition, some quinoline derivatives play an important role in wound healing. Tetrahydroquinoline derivatives are reduced forms of quinoline and are found in a variety of antibacterial, antitumor and anti-hiv drugs. Therefore, the development of a synthetic method of the structure has important significance.
Furthermore, spiro 1, 3-indendiones are considered to be a valuable functional group in pharmaceutical chemistry due to the carbonyl group which can act as a hydrogen bond acceptor. In view of the potential bioactivity of tetrahydroquinolines and the important role of 1, 3-indenedione structural units in pharmaceutical chemistry, the synthesis of spiro structures with 1, 3-indenedione and tetrahydroquinoline may generate a series of novel compounds with novel structures and significance in activity through [4+2] cycloaddition reaction of 1, 3-indenedione and 1- (benzenesulfonyl) -4-vinyl-1, 4-dihydro-2H-benzo [ d ] [1,3] oxazin-2-one.
On the other hand, tumors are diseases that seriously impair human health, and in recent years, the proportion of human death from malignant tumors has been increasing year by year due to the high tendency of tumors. Therefore, the anti-tumor lead compound and the drug with the brand new structure are found to have important theoretical significance and economic value.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide quaternary-carbon-containing indandione tetrahydroquinoline spiro alkaloids, a preparation method thereof and application thereof in preparing antitumor drugs, and the synthesis method of the compounds has the advantages of mild reaction conditions, simplicity, good substrate universality, low-cost and easily available raw materials, and the molecules have excellent antitumor cell A549, HELA and MDA-MB-231 proliferation activity. The structural formula of the quaternary carbon indandione tetrahydroquinoline spiro alkaloid is shown as the formula (I):
Wherein, R 1、R2、R3 groups are respectively hydrogen, alkyl, alkoxy, halogen, aromatic ring or condensed aromatic ring, and the substitution position is not limited. Preferably, the R 1 group is hydrogen or alkyl, the R 2 group is hydrogen or alkoxy, and the R 3 group is alkyl, alkoxy or halogen. The skeleton is 2' -phenyl-1 ' -benzenesulfonyl-4 ' -vinyl-1 ',4' -dihydro-2 ' H-spiro [ indene-2, 3' -quinoline ] -1, 3-dione, and the nitrogen atom in the skeleton is protected by a substituted benzenesulfonyl group.
The synthesis method of the compound of the formula (I) comprises the steps of taking 1- (benzenesulfonyl) -4-vinyl-1, 4-dihydro-2H-benzo [ d ] [1,3] oxazine-2-ketone compound (1) and 1, 3-indenedione compound (2) as raw materials, taking a tris (dibenzylideneacetone) dipalladium-chloroform adduct [ Pd 2(dba)3·CHCl3 ] as a catalyst, taking (R) -4- (tert-butyl) -2- (2- (diphenylphosphine) phenyl) -4, 5-dihydro-oxazole (compound 3) or 1,1 '-binaphthyl-2, 2' -Bisdiphenylphosphine (BINAP) as a ligand, reacting in a proper amount of reaction solvent under the protection of nitrogen at room temperature for 2-36 hours, and carrying out [4+2] cycloaddition reaction after removing CO 2 to obtain the target product (I).
Preferably, the synthesis method of the compound of formula (I) comprises the following steps:
Sequentially adding a catalyst, a ligand and a small amount of reaction solvent into a dry reaction container under the protection of nitrogen at room temperature, reacting for 10 minutes, then adding raw materials 1 and 2 and a proper amount of reaction solvent, reacting for 2-36 hours at room temperature, concentrating and spin-drying the solvent under reduced pressure after the reaction is finished, and purifying the product by silica gel column chromatography by using petroleum ether and ethyl acetate=5:1 (v: v) as eluent to obtain the compound shown in the formula (I).
Preferably, the reaction solvent is 1, 4-dioxane, toluene, acetonitrile, 1, 2-dichloroethane, tetrahydrofuran, chloroform or dichloromethane.
Preferably, the molar ratio of the starting 1, 3-indandione to the 1- (benzenesulfonyl) -4-ethylene-1, 4-dihydro-2H-benzo [ d ] [1,3] oxazin-2-one is 1:1.2.
Preferably, the molar ratio of the catalyst to the 1, 3-indandione compound is 0.05:1.
Preferably, the molar ratio of ligand compound 3 or BINAP to 1, 3-indandione is 0.1:1.
Compared with the prior art, the invention has the advantages that:
According to the invention, 1- (benzenesulfonyl) -4-vinyl-1, 4-dihydro-2H-benzo [ d ] [1,3] oxazine-2-one (1) and 1, 3-indenedione (2) are used as raw materials, and palladium is used for catalyzing and removing CO 2, so that an intermolecular [4+2] cycloaddition reaction occurs, and a series of tetrahydroquinoline spiro alkaloids containing quaternary carbon indandione with a complex structure are constructed. Pd 2(dba)3·CHCl3 is used as a catalyst, (R) -4- (tert-butyl) -2- (2- (diphenylphosphine) phenyl) -4, 5-dihydro-oxazole (compound 3) or BINAP is used as a ligand, the reaction is carried out for 2 to 36 hours at room temperature in a reaction solvent, and the target product (I) is obtained by [4+2] cycloaddition reaction after CO 2 is removed. Based on the synthesis method, a series of quaternary carbon-containing indandione tetrahydroquinoline spiro alkaloids with novel structure and biological activity are synthesized.
The synthesis method has the advantages of simple operation and high yield, and the method for synthesizing the tetrahydroquinoline spiro alkaloid containing quaternary carbon indandione by Pd 2(dba)3·CHCl3 -catalyzed [4+2] cycloaddition reaction by taking 1- (benzenesulfonyl) -4-vinyl-1, 4-dihydro-2H-benzo [ d ] [1,3] oxazine-2-one (1) and 1, 3-indandione (2) as raw materials is novel and has not been reported in the literature. The proliferation activity of the compounds against tumor cells A549, HELA and MDA-MB-231 is not reported in the literature.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound 4a in example 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of compound 4a in example 1;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of compound 4o in example 1;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of compound 4o in example 1;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of compound 4r in example 1;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of compound 4r in example 1;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of the compound 4w in example 1;
FIG. 8 is a nuclear magnetic resonance carbon spectrum of the compound 4w in example 1;
FIG. 9 is a nuclear magnetic resonance hydrogen spectrum of compound 4x in example 1;
FIG. 10 is a nuclear magnetic resonance carbon spectrum of compound 4x in example 1;
FIG. 11 is a nuclear magnetic resonance hydrogen spectrum of compound 4y of example 1;
FIG. 12 is a nuclear magnetic resonance carbon spectrum of compound 4y of example 1;
FIG. 13 is a nuclear magnetic resonance hydrogen spectrum of Compound 4za of example 1;
FIG. 14 is a nuclear magnetic resonance chromatogram of Compound 4za of example 1;
FIG. 15 is a single crystal-X-ray diffraction structure of compound 4a in example 1.
Detailed Description
The following specific examples are provided solely for the purpose of illustrating specific embodiments of the invention and are not intended to limit the scope of the invention as claimed. The experimental methods used in the examples described below are conventional methods unless otherwise specified, and the materials, reagents, etc. used are commercially available.
The raw material 1, 3-indene diketone compounds are all known compounds and are synthesized to [1] according to the method of literature. The raw material 1- (benzenesulfonyl) -4-vinyl-1, 4-dihydro-2H-benzo [ d ] [1,3] oxazin-2-one compound is a known compound, and is synthesized according to a literature method to obtain [2].
[1](a)E.Q.Li,Y.Huang,L.Liang,P.Z.Xie,Org.Lett.,2013,15,12,3138-3141;(b)N.Li,L.Tu,G.G.Cheng,H.L.Sa,Z.H.Li,T.Feng,Y.S.Zheng,J.K.Liu,Tetrahedron Letters,2020,61,10,151579.
[2](a)C.Wang,Y.Li,Y.Wu,Q.J.Wang,W.Y.Shi,C.H.Yuan,L.J.Zhou,Y.M.Xiao,H.C.Guo,Org.Lett.,2018,20,10,2880-2883;(b)S.N.F.B.Sh.Ismail,B.M.Yang,Y.Zhao,Org.Lett.,2021,23,8,2884-2889.
Example 1 preparation of quaternary-carbon-containing indandione tetrahydroquinoline spiro alkaloids
The preparation method of the compound 4a comprises the following steps:
Ts is p-toluenesulfonyl, and is not described in detail below.
Pd 2(dba)3·CHCl3 (0.01 mmol), BINAP (0.02 mmol) and 1, 4-dioxane (1 mL) were added in this order under nitrogen protection to the dried tube at room temperature, and after 10 minutes of reaction, raw material 1 (0.24 mmol), raw material 2 (0.2 mmol) and 1, 4-dioxane (1 mL) were added, the reaction was continued at room temperature for 24 hours, and after the completion of the reaction, the solvent was concentrated under reduced pressure and dried by spin-drying. 84.2mg of the target compound 4a are obtained by column chromatography on silica gel using petroleum ether/ethyl acetate=5:1 (v: v) as eluent, in 81% yield and with a melting point (mp) of 110–112℃.1H NMR(500MHz,CDCl3)：δ8.00(d,J＝7.9Hz,1H),7.85(d,J＝7.7Hz,1H),7.70(t,J＝7.5Hz,1H),7.59(t,J＝7.7Hz,1H),7.54–7.49(m,3H),7.41(d,J＝7.6Hz,1H),7.30–7.27(m,3H),7.07(d,J＝7.3Hz,2H),7.03–6.96(m,3H),6.88(d,J＝7.6Hz,1H),5.90(s,1H),5.09–5.02(m,1H),4.91(dd,J＝9.9,1.7Hz,1H),4.62(dd,J＝16.7,1.5Hz,1H),2.46(d,J＝10.2Hz,1H),2.42(s,3H);13C NMR(125MHz,CDCl3)：δ199.1,196.1,143.0,141.4,140.5,137.8,135.8,135.0,134.7,133.7,133.0,129.9,128.4,127.1,126.8,126.5,126.4,125.8,125.7,124.6,122.0,121.7,121.1,65.1,63.7,46.9,20.5;HRMS(ESI)m/z:[M+H]+calcd.for C32H26O4NS,520.1577;found:520.1579.
The preparation method of the compounds 4 b-4 za is the same as that of the compound 4a, the raw material feeding ratio is the same as that of the compound 4a, the reaction yields are shown in tables 1 and 2, but it should be emphasized that the compounds of the present invention are not limited to those shown in tables 1 and 2.
Tables 1 and 2 show the chemical structures of quaternary indandione tetrahydroquinoline spiro alkaloid compounds prepared from 1 and 2 (different products from different combinations of starting materials R 1、R2 and R 3).
Compound 4b yellow solid (78.1mg,yield:75％);mp 105–106℃.1H NMR(500MHz,CDCl3)：δ7.99(d,J＝8.0Hz,1H),7.84(d,J＝7.7Hz,1H),7.70(t,J＝7.9Hz,1H),7.60(t,J＝7.7Hz,1H),7.54–7.48(m,3H),7.44(d,J＝7.6Hz,1H),7.28(m,3H),6.96(d,J＝7.9Hz,2H),6.87(d,J＝7.6Hz,1H),6.82(d,J＝7.9Hz,2H),5.87(s,1H),5.09–5.01(m,1H),4.90(dd,J＝9.9,1.7Hz,1H),4.60(dd,J＝16.7,1.5Hz,1H),2.43(d,J＝10.4Hz,1H),2.41(s,3H),2.11(s,3H);13C NMR(125MHz,CDCl3)：δ200.2,197.2,143.9,142.5,141.5,140.0,136.9,135.9,135.9,135.6,134.7,134.0,130.9,129.4,128.8,128.1,127.8,127.5,126.7,126.6,125.6,123.0,122.8,122.0,66.2,64.5,47.9,21.5,21.0;HRMS(ESI)m/z:[M+H]+calcd.for C33H28NO4S,534.1734;found:534.1734.
Compound 4c yellow solid (87.4mg,yield:82％);mp 159–160℃.1H NMR(500MHz,CDCl3)：δ8.00(d,J＝8.0Hz,1H),7.85(d,J＝7.7Hz,1H),7.69(t,J＝7.5Hz,1H),7.59(t,J＝7.0Hz,1H),7.54–7.49(m,3H),7.42(d,J＝7.6Hz,1H),7.30–7.26(m,3H),6.93–6.82(m,4H),6.77(d,J＝7.0Hz,1H),5.86(s,1H),5.11–5.01(m,1H),4.90(dd,J＝10.0,1.7Hz,1H),4.61(dd,J＝16.7,1.6Hz,1H),2.44(d,J＝10.2Hz,1H),2.42(s,3H),2.07(s,3H);13C NMR(125MHz,CDCl3)：δ200.2,197.1,143.9,142.5,141.5,138.7,137.6,136.8,135.9,135.6,134.7,134.1,130.9,129.4,128.2,128.1,128.0,127.8,127.5,127.3,126.7,125.6,123.9,122.9,122.7,122.1,66.1,64.7,47.8,21.5,21.3;HRMS(ESI)m/z:[M+Na]+calcd.for C33H27NO4NaS,556.1553;found:556.1567.
TABLE 1
TABLE 2
Compound 4d yellow solid (85.3mg,yield:80％);mp 153–154℃.1H NMR(500MHz,CDCl3)：δ7.88(d,J＝7.8Hz,1H),7.81(d,J＝7.7Hz,1H),7.66(t,J＝7.3Hz,1H),7.59–7.47(m,4H),7.40(d,J＝7.6Hz,1H),7.30(t,J＝8.4Hz,3H),7.19(d,J＝7.8Hz,1H),6.97(t,J＝8.2Hz,2H),6.86(t,J＝7.2Hz,1H),6.72(d,J＝7.5Hz,1H),6.10(s,1H),5.17–5.09(m,1H),4.93(d,J＝10.0Hz,1H),4.63(d,J＝16.7Hz,1H),2.53(d,J＝10.1Hz,1H),2.42(s,3H),2.18(s,3H);13C NMR(125MHz,CDCl3)：δ200.0,197.6,143.9,142.6,141.0,137.3,136.9,136.1,135.7,135.0,134.7,133.8,130.8,130.3,129.9,129.5,128.0,127.9,127.4,127.3,126.8,125.9,125.8,122.8,122.7,122.4,66.0,60.9,47.4,21.5,19.5;HRMS(ESI)m/z:[M+Na]+calcd.for C33H27NO4NaS,556.1553;found:556.1566.
Compound 4e yellow solid (91.9mg,yield:84％);mp 153–154℃.1H NMR(500MHz,CDCl3)：δ7.99(d,J＝7.3Hz,1H),7.84(d,J＝7.7Hz,1H),7.69(t,J＝7.5Hz,1H),7.59(t,J＝7.4Hz,1H),7.55–7.47(m,3H),7.43(d,J＝7.6Hz,1H),7.29–7.26(m,3H),6.97(d,J＝8.0Hz,2H),6.87(d,J＝7.6Hz,1H),6.83(d,J＝8.1Hz,2H),5.88(s,1H),5.09–5.02(m,1H),4.90(dd,J＝10.0,1.7Hz,1H),4.61(dd,J＝16.7,1.5Hz,1H),2.45(d,J＝10.2Hz,1H),2.44–2.38(m,5H),1.03(t,J＝7.6Hz,3H);13C NMR(125MHz,CDCl3)：δ199.2,196.3,142.9,142.2,141.5,140.5,135.8,135.0,134.8,134.6,133.8,133.1,130.0,128.4,127.1,126.8,126.6,126.5,125.7,125.6,124.6,122.0,121.8,121.0,65.2,63.6,46.8,27.2,20.5,14.2;HRMS(ESI)m/z:[M+Na]+calcd.for C34H29NO4NaS,570.1710;found:570.1727.
Compound 4f as white solid (95.6mg,yield:87％);mp 120–121℃.1H NMR(500MHz,CDCl3)：δ7.97(d,J＝8.8Hz,1H),7.84(d,J＝7.7Hz,1H),7.70(t,J＝7.5Hz,1H),7.61(t,J＝7.4Hz,1H),7.54–7.48(m,3H),7.45(d,J＝7.6Hz,1H),7.30–7.26(m,3H),7.00(d,J＝8.6Hz,2H),6.87(d,J＝7.6Hz,1H),6.56(d,J＝8.8Hz,2H),5.84(s,1H),5.09–5.02(m,1H),4.90(dd,J＝9.9,1.7Hz,1H),4.61(dd,J＝16.7,1.5Hz,1H),3.62(s,3H),2.44(d,J＝10.2Hz,1H),2.42(s,3H);13C NMR(125MHz,CDCl3)：δ200.2,197.4,158.6,143.9,142.5,141.5,136.9,135.9,135.7,134.7,134.0,131.1,131.0,129.4,128.1,128.0,127.8,127.5,126.7,125.6,123.0,122.9,122.0,113.5,66.2,64.4,55.0,47.9,29.7,21.5;HRMS(ESI)m/z:[M+Na]+calcd.for C33H27NNaO5S,572.1502;found:572.1527.
Compound 4g white solid (94.4mg,yield:86％);mp 203–204℃.1H NMR(500MHz,CDCl3):δ7.99(d,J＝7.7Hz,1H),7.85(d,J＝7.7Hz,1H),7.71(t,J＝7.3Hz,1H),7.62(t,J＝7.2Hz,1H),7.54–7.49(m,3H),7.45(d,J＝7.6Hz,1H),7.30–7.27(m,3H),6.93(t,J＝7.9Hz,1H),6.87(d,J＝7.6Hz,1H),6.65(d,J＝7.7Hz,1H),6.61(s,1H),6.53(dd,J＝8.1,2.6Hz,1H),5.89(s,1H),5.09–5.02(m,1H),4.90(dd,J＝9.9,1.9Hz,1H),4.61(dd,J＝16.7,1.9Hz,1H),3.56(s,3H),2.45(d,J＝10.2Hz,1H),2.42(s,3H);13C NMR(125MHz,CDCl3)：δ200.2,197.0,159.2,144.0,142.5,141.6,140.4,136.8,136.0,135.7,134.8,134.1,130.9,129.5,129.3,128.2,127.8,127.6,126.9,125.7,123.0,122.9,122.2,119.1,113.5,112.1,66.2,64.6,55.0,47.9,21.6;HRMS(ESI)m/z:[M+Na]+calcd.for C33H27NNaO5S,572.1502;found:572.1530.
Compound 4h, white solid (84.9mg,yield:79％);mp 141–142℃.1H NMR(500MHz,CDCl3):δ7.98(d,J＝8.8Hz,1H),7.85(d,J＝7.7Hz,1H),7.72(t,J＝8.0Hz,1H),7.63(t,J＝7.9Hz,1H),7.55–7.47(m,3H),7.46(d,J＝7.6Hz,2H),7.31–7.26(m,3H),7.07(dd,J＝8.5,5.2Hz,1H),6.88(d,J＝7.6Hz,1H),6.72(t,J＝8.7Hz,2H),5.87(s,1H),5.08–5.01(m,1H),4.91(dd,J＝9.9,1.7Hz,1H),4.62(dd,J＝16.7,1.5Hz,1H),2.44(d,J＝10.6Hz,1H),2.42(s,3H);13C NMR(125MHz,CDCl3)：δ200.0,197.2,161.8(d,J＝246.2Hz),144.1,142.3,141.5,136.7,135.9,134.8(d,J＝3.2Hz),134.5,133.8,130.8,129.5,128.6(d,J＝8.2Hz),128.2,127.7,127.5,126.9,125.7,123.1,122.9,122.2,115.1(d,J＝21.6Hz),66.1,64.1,47.9,21.5;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O4NFNaS,560.1302;found:560.1320.
Compound 4i as white solid (81.6mg,yield:76％);mp 123–124℃.1H NMR(500MHz,CDCl3)：δ8.00(d,J＝8.5Hz,1H),7.86(d,J＝7.7Hz,1H),7.73(t,J＝7.1Hz,1H),7.63(t,J＝7.1Hz,1H),7.54–7.50(m,3H),7.46(d,J＝7.6Hz,1H),7.31–7.27(m,3H),7.01–6.95(m,1H),6.89–6.82(m,3H),6.69(t,J＝8.3Hz,1H),5.89(s,1H),5.08–5.01(m 1H),4.91(dd,J＝9.9,1.6Hz,1H),4.61(dd,J＝16.7,1.4Hz,1H),2.43(d,J＝10.0Hz,1H),2.42(s,3H);13C NMR(125MHz,CDCl3)：δ199.8,196.8,162.4(d,J＝246.5Hz),144.1,142.3,141.5(d,J＝6.9Hz),141.4,136.5,136.0(d,J＝28.6Hz),134.4,133.8,130.7,129.7(d,J＝8.2Hz),129.5,128.3,127.7,127.5,126.9,125.6,123.1,122.8,122.3,114.5(d,J＝21.1Hz),114.1(d,J＝22.7Hz),65.9,63.9,48.0,21.5;HRMS(ESI)m/z:[M+H]+calcd.for C32H25O4NFS,538.1483;found:538.1482.
Compound 4j yellow solid (91.3mg,yield:85％);mp 123–124℃.1H NMR(500MHz,CDCl3)：δ7.93(d,J＝7.9Hz,1H),7.87(d,J＝7.7Hz,1H),7.71(t,J＝7.5Hz,1H),7.61(d,J＝7.9Hz,2H),7.58(d,J＝7.5Hz,1H),7.51(t,J＝7.7Hz,1H),7.42–7.35(m,2H),7.36–7.28(m,3H),7.09(t,J＝8.1Hz,1H),6.99–6.88(m,3H),6.36(s,1H),5.18–5.09(m,1H),4.93(d,J＝10.0Hz,1H),4.61(d,J＝18.0Hz,1H),2.53(d,J＝10.1Hz,1H),2.44(s,3H);13C NMR(125MHz,CDCl3)：δ199.0,197.7,144.1,141.9,137.2,136.6,135.9,135.8,135.1,134.7,131.5,131.0,130.6,129.6 128.7,128.7,128.1,127.6,127.1,126.9,125.9,123.2,122.8,122.6,65.7,60.3,47.3,21.6;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O4NFNaS,560.1302;found,560.1323.
Compound 4k brown solid (75.0mg,yield:64％);mp 120–121℃.1H NMR(500MHz,CDCl3)：δ8.01(d,J＝7.9Hz,1H),7.86(d,J＝7.7Hz,1H),7.73(t,J＝7.4Hz,1H),7.63(t,J＝7.4Hz,1H),7.54–7.51(m,3H),7.46(d,J＝7.6Hz,1H),7.31–7.27(m,5H),7.24(d,J＝8.1Hz,2H),6.88(d,J＝7.5Hz,1H),5.95(s,1H),5.08–5.00(m,1H),4.92(dd,J＝10.0,1.7Hz,1H),4.62(dd,J＝16.7,1.8Hz,1H),2.45(d,J＝10.3Hz,1H),2.42(s,3H);13C NMR(125MHz,CDCl3)：δ199.7,196.9,144.3,143.1,142.2,141.5,136.6,136.3,136.1,134.4,133.7,130.6,129.6,128.4,127.7,127.6,127.3,127.1,125.7,125.3,125.2,123.2,123.0,122.4,66.1,64.0,48.2,21.6;HRMS(ESI)m/z:[M+Na]+calcd.for C33H24O4NF3NaS,610.1270;found:610.1288.
Compound 4l white solid (86.0mg,yield:72％);mp 159–160℃.1H NMR(500MHz,CDCl3)：δ7.98(d,J＝8.0Hz,1H),7.85(d,J＝7.7Hz,1H),7.73(t,J＝7.5Hz,1H),7.66(t,J＝7.2Hz,1H),7.54–7.46(m,4H),7.31–7.26(m,3H),7.17(d,J＝8.6Hz,2H),6.98(d,J＝8.4Hz,2H),6.87(d,J＝7.6Hz,1H),5.84(s,1H),5.07–5.00(m,1H),4.91(dd,J＝9.9,1.7Hz,1H),4.61(dd,J＝16.7,1.5Hz,1H),2.43(d,J＝10.5Hz,1H),2.42(s,3H);13C NMR(125MHz,CDCl3)：δ199.8,197.0,144.1,142.3,141.5,138.1,136.6,136.2,135.9,134.5,133.7,131.3,130.7,129.5,128.6,128.3,127.7,127.5,126.9,125.6,123.1,123.0,122.3,121.5,66.0,64.0,48.1,21.5;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O4NBrNaS,620.0502;found:620.0521.
Compound 4m white solid (88.5mg,yield:80％);mp 233–234℃.1H NMR(500MHz,CDCl3)：δ7.94(d,J＝7.2Hz,1H),7.88(d,J＝7.7Hz,1H),7.72(t,J＝7.5Hz,1H),7.64–7.58(m,3H),7.51(t,J＝7.8Hz,1H),7.40(d,J＝7.7Hz,1H),7.38(d,J＝8.0Hz,1H),7.34–7.32(m,3H),7.10(t,J＝7.4Hz,1H),6.98–6.90(m,3H),6.35(s,1H),5.16–5.09(m,1H),4.93(dd,J＝10.0,1.8Hz,1H),4.62(dd,J＝16.7,1.5Hz,2H),2.53(d,J＝10.1Hz,1H),2.44(s,3H);13C NMR(125MHz,CDCl3)：δ198.9,197.6,144.0,141.8,137.2,136.6,135.9,135.8,135.1,134.7,131.4,131.0,130.6,129.6,128.7,128.7,128.1,127.6,127.1,126.9,125.9,123.1,122.7,122.6,65.7,60.3,47.3,21.6;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O4NClNaS,576.1007;found,576.1022.
Compound 4n as white solid (85.0mg,yield:71％);mp 110–111℃.1H NMR(500MHz,CDCl3)：δ8.04(d,J＝7.9Hz,1H),7.87(d,J＝7.7Hz,1H),7.71(t,J＝7.5Hz,1H),7.59(t,J＝7.5Hz,1H),7.56(d,J＝8.3Hz,2H),7.53(d,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.40(d,J＝7.2Hz,2H),7.33(t,J＝7.6Hz,2H),7.30(d,J＝7.9Hz,3H),7.28–7.26(m,3H),7.16(d,J＝8.1Hz,2H),6.90(d,J＝7.6Hz,1H),5.96(s,1H),5.12–5.04(m,1H),4.92(dd,J＝9.9,1.7Hz,1H),4.64(dd,J＝16.7,1.5Hz,1H),2.49(d,J＝10.1Hz,1H),2.43(s,3H);13C NMR(125MHz,CDCl3)：δ200.1,197.2,144.0,142.4,141.5,140.4,140.0,137.9,136.8,136.0,135.7,134.6,134.0,130.9,129.4,128.6,128.2,127.8,127.5,127.2,126.8,126.8,125.6,123.0,122.9,122.1,66.2,64.5,48.0,21.5;HRMS(ESI)m/z:[M+Na]+calcd.for C38H29O4NNaS,618.1710;found:618.1735.
Compound 4o, white solid (85.4mg,yield:80％);mp 183–184℃.1H NMR(500MHz,CDCl3)：δ7.91(t,J＝7.9Hz,2H),7.83(dd,J＝12.2,7.7Hz,1H),7.76–7.67(m,1.5H),7.64(t,J＝7.4Hz,1H),7.60(t,J＝7.4Hz,0.5H),7.55(t,J＝8.2Hz,2H),7.48(d,J＝8.3Hz,2H),7.44(d,J＝7.6Hz,0.5H),7.36(t,J＝7.8Hz,0.5H),7.35–7.28(m,2H),7.21–7.12(m,4H),7.08–6.96(m,6.5H),6.01(s,1H),5.95(s,0.5H),5.48–5.41(m,1H),5.36–5.27(m,0.5H),4.82(d,J＝10.1Hz,1H),4.73(dd,J＝9.9,1.7Hz,0.5H),4.64(d,J＝16.9Hz,1H),4.47(dd,J＝16.7,1.7Hz,0.5H),3.51(d,J＝7.7Hz,1H),2.66(d,J＝10.9Hz,0.5H),2.44(s,1.5H),2.36(s,3H),2.15(s,1.5H),2.02(s,3H);13C NMR(125MHz,CDCl3)：δ200.42,197.92,197.49,196.35,143.86,143.65,142.68,141.81,140.41,140.31,138.99,138.97,137.49,137.39,136.44,136.13,136.03,135.88,135.84,135.68,135.10,134.22,131.90,131.75,131.24,129.34,129.31,128.83,128.10,128.03,127.86,127.58,127.51,127.50,127.40,127.30,127.14,126.74,126.67,123.60,123.59,122.94,122.75,122.33,119.51,118.75,67.22,64.53,64.20,60.81,49.99,45.19,22.95,21.53,21.47,18.81;HRMS(ESI)m/z:[M+Na]+calcd.for C33H27O4NNaS,556.1553;found:556.1579.
Compound 4p yellow solid (86.4mg,yield:81％);mp 229–230℃.1H NMR(500MHz,CDCl3)：δ8.00(d,J＝9.0Hz,1H),7.85(d,J＝7.7Hz,1H),7.70(t,J＝7.5Hz,1H),7.60(t,J＝7.4Hz,1H),7.56–7.46(m,3H),7.43(d,J＝7.6Hz,1H),7.30–7.27(m,4H),6.94–6.84(m,3H),6.83(s,1H),6.78(d,J＝7.2Hz,1H),5.86(s,1H),5.10–5.02(m,1H),4.91(dd,J＝9.9,1.8Hz,1H),4.61(dd,J＝16.7,1.8Hz,1H),2.45(d,J＝10.1Hz,1H),2.42(s,3H),2.07(s,3H);13C NMR(125MHz,CDCl3)：δ200.3,197.1,143.9,142.5,141.6,138.7,137.6,136.8,135.9,135.6,134.7,134.1,131.0,129.4,128.2,128.1,128.0,127.8,127.5,127.3,126.7,125.6,123.9,122.9,122.8,122.1,66.2,64.8,47.8,21.5,21.3;HRMS(ESI)m/z:[M+Na]+calcd.for C33H27O4NNaS,556.1553;found:556.1567.
Compound 4q yellow solid (83.9mg,yield:78％);mp 138–139℃.1H NMR(500MHz,CDCl3)：δ7.96(dd,J＝8.7,5.1Hz,1H),7.85(d,J＝7.6Hz,1H),7.71(t,J＝7.4Hz,1H),7.61(t,J＝7.4Hz,1H),7.55(d,J＝8.1Hz,2H),7.43(d,J＝7.6Hz,1H),7.32(d,J＝8.0Hz,2H),7.21–7.17(m,1H),7.04–6.99(m,5H),6.60(d,J＝6.9Hz,1H),5.87(s,1H),5.04–4.92(m,2H),4.61(d,J＝16.5Hz,1H),2.43(s,3H),2.38(d,J＝9.7Hz,1H);13C NMR(125MHz,CDCl3)：δ198.9,196.1,160.3(d,J＝246.7Hz),143.2,141.4,140.5,137.6,135.6(d,J＝8.2Hz),135.1,134.8,133.4,131.7(d,J＝2.8Hz),129.1,128.5,128.4,127.2,126.6,125.7,122.1,121.8(d,J＝3.8Hz),113.8(d,J＝22.5Hz),112.1(d,J＝24.5Hz),64.8,63.8,46.5,20.5;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O4NFNaS,560.1302;found:560.1291.
Compound 4r as white solid (89.8mg,yield:81％);mp 109–110℃.1H NMR(500MHz,CDCl3)：δ7.93(d,J＝8.5Hz,1H),7.85(d,J＝7.7Hz,1H),7.71(t,J＝7.4Hz,1H),7.61(t,J＝7.4Hz,1H),7.56(d,J＝8.1Hz,2H),7.49–7.40(m,2H),7.32(d,J＝8.0Hz,2H),7.07–6.96(m,5H),6.86(s,1H),5.86(s,1H),5.08–4.91(m,2H),4.63(d,J＝16.1Hz,1H),2.43(s,3H),2.41(d,J＝9.0Hz,1H);13C NMR(125MHz,CDCl3)：δ199.8,197.1,144.2,142.3,141.5,138.4,136.1,135.9,135.9,135.5,134.5,132.5,130.1,129.6,128.8,127.6,127.5,126.7,126.0,123.1,122.9,122.8,65.7,64.8,47.5,21.5;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O4NClNaS,576.1007;found:576.1019.
Compound 4s, white solid (87.5mg,yield:79％);mp 229–230℃.1H NMR(500MHz,DMSO-d6)：δ7.97–7.89(m,2H),7.88(d,J＝2.2Hz,1H),7.81(td,J＝7.4,1.3Hz,1H),7.50(d,J＝7.6Hz,1H),7.48(s,3H),7.40(dd,J＝8.2,2.2Hz,1H),7.12(dd,J＝8.9,1.9Hz,1H),7.09(d,J＝7.7Hz,2H),7.06(d,J＝7.1Hz,1H),6.96(d,J＝7.1Hz,2H),6.88(dd,J＝8.2,1.2Hz,1H),5.76(s,1H),5.09–5.02(m,1H),4.96(dd,J＝9.9,1.9Hz,1H),4.55(dd,J＝16.4,1.9Hz,1H),2.41(s,3H),2.3(d,J＝10.3Hz,1H);13C NMR(125MHz,DMSO-d6)：δ199.5,197.0,145.4,142.0,141.2,138.8,138.1,137.7,137.5,133.9,133.3,132.5,130.7,130.5,128.7,128.1,127.8,127.5,127.4,127.2,126.7,123.8,123.3,123.2,65.7,64.5,47.6,21.5;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O4NClNaS,576.1007;found:576.1027.
Compound 4t, white solid (91.0mg,yield:76％);mp 155–156℃.1H NMR(500MHz,CDCl3)：δ7.90–7.83(m,2H),7.72(t,J＝7.5Hz,1H),7.66–7.60(m,2H),7.56(d,J＝8.3Hz,2H),7.44(d,J＝7.6Hz,1H),7.33(d,J＝8.0Hz,2H),7.06–6.93(m,6H),5.85(s,1H),5.04–4.93(m,2H),4.63(dd,J＝16.4,1.8Hz,1H),2.44(s,3H),2.42(d,J＝9.0Hz,1H);13C NMR(125MHz,CDCl3)：δ198.8,196.1,143.3,141.4,140.5,137.4,135.1,135.1,135.0,134.8,133.5,130.2,129.1,128.6,128.1,127.8,127.2,126.6,126.5,125.7,122.1,121.9,121.8,119.6,64.8,63.8,46.4,20.5;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O4NBrNaS,620.0502;found:620.0502.
Compound 4u yellow solid (91.0mg,yield:85％);mp 235–236℃.1H NMR(500MHz,CDCl3)：δ8.00(d,J＝8.0Hz,1H),7.85(d,J＝7.7Hz,1H),7.69(t,J＝7.9Hz,1H),7.61–7.56(m,3H),7.50(t,J＝7.7Hz,1H),7.41(d,J＝7.6Hz,1H),7.27(t,J＝7.0Hz,1H),7.08(d,J＝7.1Hz,2H),7.04–6.92(m,5H),6.89(d,J＝7.6Hz,1H),5.90(s,1H),5.13–5.02(m,1H),4.92(dd,J＝10.0,1.7Hz,1H),4.70(dd,J＝16.7,1.5Hz,1H),3.84(s,3H),2.58(d,J＝10.1Hz,1H);13C NMR(125MHz,CDCl3)：δ200.3,197.3,163.4,142.5,141.6,139.0,136.9,136.0,135.8,134.0,131.0,129.7,129.6,128.2,127.8,127.5,126.8,125.7,123.1,122.8,122.3,114.0,66.2,64.7,55.7,48.0;HRMS(ESI)m/z:[M+Na]+calcd.for C32H25O5NNaS,558.1346;found:558.1362.
Compound 4v, white solid (86.0mg,yield:70％);mp 232–233℃.1H NMR(500MHz,CDCl3)：δ7.98(d,J＝7.2Hz,1H),7.85(d,J＝7.7Hz,1H),7.73(t,J＝7.8Hz,1H),7.65(t,J＝7.0Hz,1H),7.59–7.53(m,2H),7.53–7.46(m,2H),7.28(d,J＝6.9Hz,1H),7.16(d,J＝8.5Hz,2H),7.02–6.95(m,2H),6.94(d,J＝8.9Hz,2H),6.88(d,J＝7.6Hz,1H),5.84(s,1H),5.09–5.02(m,1H),4.92(dd,J＝9.9,1.8Hz,1H),4.69(dd,J＝16.7,1.8Hz,1H),3.85(s,3H),2.55(d,J＝10.1Hz,1H);13C NMR(125MHz,CDCl3)：δ199.9,197.0,163.5,142.3,141.4,138.2,136.7,136.2,136.0,133.6,131.3,130.7,129.6,129.2,128.6,128.2,127.6,126.9,125.7,123.1,123.0,122.4,121.5,114.0,65.9,63.9,55.7,48.1;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O5NBrNaS,636.0451;found:636.0476.
Compound 4w brown solid (91.6mg,yield:81％);mp 188–189℃.1H NMR(500MHz,CDCl3)：δ7.97(d,J＝7.9Hz,1H),7.84(d,J＝7.7Hz,1H),7.70(t,J＝7.4Hz,1H),7.65–7.58(m,1H),7.57(d,J＝8.8Hz,2H),7.51–7.43(m,2H),,7.26(d,J＝15.1Hz,1H),7.00(d,J＝8.5Hz,2H),6.94(d,J＝8.9Hz,2H),6.88(d,J＝7.6Hz,1H),6.56(d,J＝8.7Hz,2H),5.84(s,1H),5.11–5.03(m,1H),4.92(d,J＝10.0Hz,1H),4.69(d,J＝16.7Hz,1H),3.85(s,3H),3.62(s,3H),2.57(d,J＝10.1Hz,1H);13C NMR(125MHz,CDCl3)：δ199.3,196.4,162.3,157.5,141.5,140.5,135.9,134.9,134.6,132.9,130.1,130.0,128.6,128.6,127.1,127.0,126.7,125.7,124.6,122.0,121.8,121.1,112.9,112.5,65.2,63.3,54.6,54.0,46.9;HRMS(ESI)m/z:[M+Na]+calcd.for C33H27O6NNaS,588.1451;found:588.1476.
Compound 4x white solid (107.1mg,yield:87％);mp 123–124℃.1H NMR(500MHz,CDCl3)：δ8.05(d,J＝7.6Hz,1H),7.83(d,J＝7.7Hz,1H),7.61–7.58(m,3H),7.52(t,J＝7.7Hz,1H),7.47–7.43(m,3H),7.39(d,J＝8.6Hz,1H),7.33–7.26(m,2H),7.19(d,J＝8.0Hz,1H),6.97–6.89(m,4H),6.87(d,J＝2.1Hz,1H),6.05(s,1H),5.11–5.04(m,1H),4.92(d,J＝11.5Hz,1H),4.71(d,J＝17.9Hz,1H),3.79(s,3H),3.75(s,3H),2.62(d,J＝10.1Hz,1H);13C NMR(125MHz,CDCl3)：δ200.3,197.3,163.4,157.7,142.4,141.5,137.1,136.0,135.8,134.3,134.1,133.8,131.0,129.7,129.6,129.6,128.3,128.2,127.9,126.9,126.9,125.8,125.5,123.0,122.9,122.3,118.7,114.0,105.4,66.4,64.8,55.7,55.2,48.2;HRMS(ESI)m/z:[M+Na]+calcd.for C37H29O6NNaS,638.1608;found:638.1627.
Compound 4y as white solid (90.5mg,yield:75％);mp 135–136℃.1H NMR(500MHz,CDCl3)：δ8.01(d,J＝7.8Hz,1H),7.87(d,J＝7.7Hz,1H),7.73(t,J＝7.4Hz,1H),7.64(t,J＝7.4Hz,1H),7.58(d,J＝8.9Hz,2H),7.52(t,J＝7.7Hz,1H),7.46(d,J＝7.6Hz,1H),7.30(t,J＝7.4Hz,3H),7.24(d,J＝8.0Hz,2H),6.95(d,J＝8.9Hz,2H),6.90(d,J＝7.6Hz,1H),5.95(s,1H),5.10–5.02(m,1H),4.93(d,J＝10.0Hz,1H),4.70(d,J＝16.6Hz,1H),3.84(s,3H),2.57(d,J＝10.1Hz,1H);13C NMR(125MHz,CDCl3)：δ199.7,196.9,163.6,143.1,142.2,141.4,136.6,136.3,136.1,133.6,130.6,129.6,129.1,128.3,127.7,127.3,127.0,125.8,125.2,125.2,123.2,123.0,122.5,114.1,66.0,64.0,55.7,48.2;HRMS(ESI)m/z:[M+Na]+calcd.for C33H24O5NF3NaS,626.1219;found:626.1237.
Compound 4z white solid (93.5mg,yield:82％);mp 134–135℃.1H NMR(500MHz,CDCl3)：δ7.98(d,J＝7.9Hz,1H),7.85(d,J＝7.6Hz,1H),7.72(t,J＝7.4Hz,1H),7.63(t,J＝7.4Hz,1H),7.57(d,J＝8.8Hz,2H),7.49(q,J＝7.6Hz,2H),7.27(d,J＝14.9Hz,1H),7.05(d,J＝8.3Hz,2H),7.00(d,J＝8.4Hz,2H),6.94(d,J＝8.8Hz,2H),6.89(d,J＝7.5Hz,1H),5.87(s,1H),5.09–5.02(m,1H),4.92(d,J＝9.9Hz,1H),4.69(d,J＝16.6Hz,1H),3.83(s,3H),2.55(d,J＝10.1Hz,1H);13C NMR(125MHz,CDCl3)：δ199.9,197.1,163.5,142.2,141.4,137.7,136.7,136.2,136.0,133.6,133.2,130.7,129.6,129.2,128.3,128.3,128.2,127.6,126.9,125.7,123.1,122.9,122.4,114.0,66.0,63.9,55.7,48.1;HRMS(ESI)m/z:[M+Na]+calcd.for C32H24O5NClNaS,592.0956;found:592.0973.
Compound 4za, white solid (74.3mg,yield:71％);mp 140–141℃.1H NMR(500MHz,CDCl3)：δ8.00(d,J＝7.4Hz,1H),7.86(d,J＝7.7Hz,1H),7.73–7.65(m,3H),7.61(t,J＝7.4Hz,1H),7.52(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.29(t,J＝7.8Hz,1H),7.17(t,J＝8.5Hz,2H),7.09–6.99(m,5H),6.91(d,J＝7.6Hz,1H),5.88(s,1H),5.11–5.04(m,1H),4.94(dd,J＝10.0,1.4Hz,1H),4.73(d,J＝16.7Hz,1H),2.54(d,J＝10.1Hz,1H);13C NMR(125MHz,CHCl3)：δ200.1,197.1,165.5(d,J＝255.7Hz),142.5,141.5,138.6,136.5,136.1,135.8,133.9,133.8,130.6,130.2(d,J＝9.2Hz),128.3,128.2,127.7(d,J＝11.9Hz),127.0,126.7,125.9,123.1,122.8,122.5,116.1(d,J＝22.5Hz),66.1,64.9,48.0;HRMS(ESI)m/z:[M+Na]+calcd.for C31H22O4NFNaS,546.1146;found:546.1171.
EXAMPLE 2 cytotoxicity assay
The compound shown in the formula (1) has important biological activity for resisting tumor cell proliferation, and cytotoxicity tests on in-vitro tumor cells of human lung cancer cells A549, cervical cancer cells HELA and human breast cancer cells MDA-MB-231 show that the quaternary carbon indandione-containing tetrahydroquinoline spiro alkaloid compound shown in the formula (1) has obvious inhibition effect on tumor cell growth and can possibly be developed into a novel antitumor drug.
1. Experimental materials
Human lung cancer cells A549, cervical cancer cells Hela, and human breast cancer cells MDA-MB-231 used in this experiment were purchased from European certified cell culture collection, RPMI1640 medium was purchased from Hyclone, U.S. A., fetal Bovine Serum (FBS) was purchased from Biontech, penicillin-streptomycin solution (100X) was purchased from Biyun biotechnology Co., ltd, and tetramethylthiazole blue (MTT) and dimethyl sulfoxide were purchased from Sigma-Aldrich, U.S.A.
2. Experimental method
2.1 Cell culture
A549, hela and MDA-MB-231 cells were cultured in an incubator containing 10% Fetal Bovine Serum (FBS) and 1% penicillin-streptomycin in RPMI-1640 complete medium at 37 ℃ with humidity 45-65% and 5% CO 2, respectively. When the cells grow to the logarithmic growth phase, passaging, experiments and cryopreservation are performed.
2.2MTT method for detecting cell viability
Cell plating and dosing cells in the logarithmic growth phase were collected, seeded at a density of 3X 10 3 cells/well in 96-well plates and incubated in a 37℃5% CO 2 cell incubator for 24h. The next day, old medium in wells was aspirated, and the DMSO-dissolved test compounds were diluted with RPMI-1640 medium to the corresponding concentrations and added to 96-well plates, 100 μl per well, with 3 duplicate wells per concentration, and each plate was simultaneously set with normal cell groups (cell-only and 1640 medium) and blank control groups (cell-free medium). After dosing, 96-well plates were incubated in a cell incubator at 37 ℃ with 5% CO 2 for 72h.
Cell viability assay after 72h incubation, 20. Mu.L MTT solution (5 mg/mL) was added to each well and incubated again for 1.5h. Subsequently, the medium in the well plate was removed, 150. Mu.L of DMSO was added to each well, and the mixture was placed on a horizontal shaker and shaken at medium speed for 5 minutes, and absorbance at 562nm was measured using a microplate reader.
Data processing, namely calculating the relative inhibition rate of the drug to the cell growth according to the following formula:
Cell inhibition ratio = [1- (X-C0)/(C-C0) ] ×100%
Wherein C, C and X represent the average absorbance values of the normal cell group, the blank group and the drug-treated group, respectively. Finally, the cell inhibition curve was fitted using GRAPHPAD PRISM 5.0.0 software and the IC 50 values of the cell growth inhibition of the test compounds were calculated.
2.3 Experimental results
Compound 4za had an IC 50 of 3.108 μmol/L for a549 tumor cells and the positive control cisplatin had an IC 50 of 22.0 μmol/L for a549 tumor cells.
Compound 4za had an IC 50 of 0.821 μmol/L for Hela cells, compound 4o had an IC 50 of 4.075 μmol/L for Hela cells, compound 4y had an IC 50 of 1.437 μmol/L for Hela cells, and positive control cisplatin had an IC 50 of 5.32 μmol/L for Hela tumor cells.
Compound 4r was 1.292. Mu. Mol/L for IC 50 of MDA-MB-231 cells, compound 4za was 0.656. Mu. Mol/L for IC 50 of MDA-MB-231 cells, compound 4w was 1.655. Mu. Mol/L for IC 50 of MDA-MB-231 cells, compound 4x was 2.215. Mu. Mol/L for IC 50 of MDA-MB-231 cells, and positive control cisplatin was 2.87. Mu. Mol/L for IC 50 of MDA-MB-231 cells.
TABLE 3 IC 50 values of the respective Compounds for tumor cells A549, HELA and MDA-MB-231
3. Conclusion of the experiment
A549, hela, MDA-MB-231 cells are effective tools and evaluation indicators for testing cytotoxicity of compounds against tumor cells. The experiment shows that the quaternary carbon indandione tetrahydroquinoline spiro alkaloid compound shown in the formula (1) has certain cytotoxicity to A549, hela and MDA-MB-231 cells, and can be possibly developed into a novel medicament with an anti-tumor effect.
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