茚并异喹啉酮N-杂化衍生物的合成及其拓扑异构酶I抑制和抗肿瘤活性研究

doi:10.6023/cjoc202504029

摘要/Abstract

以具有良好拓扑异构酶I (Topo I)抑制和抗肿瘤活性的茚并异喹啉酮骨架为参考, 根据电子等排替换及优势结构等药物设计理论, 以邻氨基苯甲酸衍生物及邻甲酰基苯甲酸等为原料, 合成了30个新的异吲哚并喹唑啉酮化合物, 亦即茚并异喹啉酮的N-杂化合物, 并研究了它们对人肺癌细胞NCI-H460、宫颈癌细胞HeLa和胃癌细胞MGC-803的体外生长抑制及对Topo I的抑制活性. 结果表明, 只有少数目标化合物在较高浓度时显示出一定的Topo I抑制活性, 且大多数目标化合物对受试肿瘤细胞株的细胞毒性均比较弱. 通过分子对接并与母体化合物茚并异喹啉进行比较, 发现设计合成的N-杂化合物与Topo I/DNA的结合模式跟母体化合物不同, 推测其非平面的多芳香环骨架结构可能是影响其Topo I结合模式及抑制活性, 进而显示出较弱的细胞毒活性的关键因素.

关键词: 茚并异喹啉酮, 电子等排体, 拓扑异构酶I抑制剂, 抗肿瘤活性

Based on the drug design theory of electronic isodisplacement and dominant structure, using the indeno isoquinoline ketone skeleton with good topoisomerase I (Topo I) inhibition and anti-tumor activity as a reference, 30 new indole isoquinoline ketone compounds, namely N-heterocyclic compounds of indeno isoquinoline ketone, were synthesized using derivatives of ortho-aminobenzoic acid and ortho-formylbenzoic acid as raw materials. Their anti-proliferative activity against the NCI-H460, HeLa, and MGC-803 cancer cell lines were assessed in vitro, and their Topo I inhibitory activity was evaluated. The results showed that only a few target compounds exhibited certain Topo I inhibitory activity at high concentrations, and most of the target compounds displayed weak cytotoxicity against the tested tumor cell lines. Through molecular docking and comparison with the parent compound indenoisoquinoline, it was found that the binding mode of the aza-analogues with Topo I/DNA was different from that of the parent compound, speculating that its nonplanar backbone might be the key factor affecting its Topo I binding mode and inhibitory activity, and then resulted in their weak cytotoxic activity.

Key words: indenoisoquinoline, bio-isosterism, Topo I inhibitor, antitumor activity

引用此文

郑彬, 韦敏, 林雯雯, 潘成学. 茚并异喹啉酮N-杂化衍生物的合成及其拓扑异构酶I抑制和抗肿瘤活性研究[J]. 有机化学, 2025, 45(8): 2815-2824.

Bin Zheng, Min Wei, Wenwen Lin, Chengxue Pan. Synthesis, Topo I Inhibition and Antitumor Evaluation of Aza-indenoisoquinoline Derivatives[J]. Chinese Journal of Organic Chemistry, 2025, 45(8): 2815-2824.

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参考文献 25

[1]	Buzun, K.; Bielawska, A.; Bielawski, K.; Gornowicz, A. J. Enzyme Inhib. Med. Chem. 2020, 35, 1781.
[2]	Verma, R. P.; Hansch, C. Chem. Rev. 2009, 109, 213.
[3]	Zheng, B.; Wang, Y.-X.; Wu, Z.-Y.; Li, X.-W.; Qin, L.-Q.; Chen, N.-Y.; Su, G.-F.; Su, J.-C.; Pan, C.-X. Molecules 2025, 30, 894.
[4]	Hu, M.-H.; Lin, J.-H. J. Med. Chem. 2021, 64, 6720.
[5]	Niu, S. X.; Tang, Z. C.; Liu, C.; Wang, T. L.; You, Q. D.; Xiang, H. Chin. J. Org. Chem. 2015, 35, 2150 (in Chinese).
	(牛绍雄, 唐智超, 刘畅, 王天麟, 尤启冬, 向华, 有机化学, 2015, 35, 2150.) doi: 10.6023/cjoc201504004
[6]	Cong, H.; Wu, X. M.; Xu, J. Y. Pharm. Clin. Res. 2014, 22, 239 (in Chinese).
	(丛蔚, 吴晓明, 徐进宜, 药学与临床研究, 2014, 22, 239.)
[7]	Zhang, S. M.; Sun, H. P.; Jia, J. M.; Xu, X. L.; You, Q. D. J. Chin. Pharm. Univ. 2013, 44, 589 (in Chinese).
	(张圣淼, 孙昊鹏, 贾剑敏, 徐晓莉, 尤启冬, 中国药科大学学报, 2013, 44, 589.)
[8]	Cushman, M. J. Med. Chem. 2021, 64, 17572. doi: 10.1021/acs.jmedchem.1c01491 pmid: 34879200
[9]	Wang, K.-B.; Elsayed, M. S. A.; Wu, G.; Deng, N.; Cushman, M.; Yang, D. J. Am. Chem. Soc. 2019, 141, 11059.
[10]	Morrell, A.; Placzek, M.; Parmley, S.; Grella, B.; Antony, S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2007, 50, 4388. pmid: 17676830
[11]	Beck, D. E.; Reddy, P. V. N.; Lv, W.; Abdelmalak, M.; Tender, G. S.; Lopez, S.; Agama, K.; Marchand, C.; Pommier, Y.; Cushman, M. J. Med. Chem. 2016, 59, 3840.
[12]	Li, X. W.; Fang, S. J.; Li, Y. Z.; Qin, L. Q.; Chen, N. Y.; Zheng, B.; Mo, D. L.; Su, G. F.; Su, J. C.; Pan, C. X. Bioorg. Chem. 2024, 143, 107015.
[13]	Yuan, J. M.; Wei, K.; Zhang, G. H.; Chen, N. Y.; Wei, X. W.; Pan, C. X.; Mo, D. L.; Su, G. F. Eur. J. Med. Chem. 2019, 169, 144.
[14]	Liu, Q. Q.; Lu, K.; Zhu, H. M.; Kong, S. L.; Yuan, J. M.; Zhang, G. H.; Chen, N. Y.; Gu, C. X.; Pan, C. X.; Mo, D. L.; Su, G. F. Eur. J. Med. Chem. 2019, 165, 293.
[15]	Huang, W. Y.; Zhang, X. R.; Lyu, L.; Wang, S. Q.; Zhang, X. T. Bioorg. Chem. 2020, 99, 103814.
[16]	Devi, R. V.; Garande, A. M.; Bhate, P. M. Synlett 2016, 27, 2807.
[17]	Kolotaev, A. V.; Matevosyan, K. R.; Osipov, V. N.; Khachatryan, D. S. Tetrahedron Lett. 2019, 60, 151315.
[18]	Lohar, T.; Mane, A.; Kamat, S.; Kumbhar, A.; Salunkhe, R. Res. Chem. Intermed. 2018, 44, 1919.
[19]	Cushman, M.; Jayaraman, M.; Vroman, J. A.; Fukunaga, A. K.; Fox, B, M.; Kohlhagen, G.; Strumberg, D.; Pommier, Y. J. Med. Chem. 2000, 43, 3688. pmid: 11020283
[20]	Han, Y.; Buric, A.; Chintareddy, V.; DeMoss, M.; Chen, L.; Dickerhoff, J.; De Dios, R.; Chand, P.; Riggs, R.; Yang, D.; Cushman, M. J. Med. Chem. 2024, 67, 7006.
[21]	Staker, B. L.; Feese, M. D.; Cushman, M.; Pommier, Y.; Zembower, D.; Stewart, L.; Burgin, A. B. J. Med. Chem. 2005, 48, 2336. pmid: 15801827
[22]	Darras, F. H.; Kling, B.; Heilmann, J.; Decker, M. ACS Med. Chem. Lett. 2012, 3, 914. doi: 10.1021/ml3001825 pmid: 24900407
[23]	Reissenweber, G.; Mangold, D. Angew. Chem., Int. Ed. 1980, 92, 196.
[24]	Madhubabu, M. V.; Shankar, R.; Reddy, G. R.; Rao, T. S.; Rao, M. V.; Akula, R. Tetrahedron Lett. 2016, 57, 5033.
[25]	Yang, X.; Wang, Z. P.; Xiang, S.; Wang, D.; Zhao, Y.; Luo, D.; Qiu, Y.; Huang, C.; Guo, J.; Dai, Y.; Zhang, S. L.; He, Y. J. Med. Chem. 2022, 65, 8040.

Compd.	IC₅₀/(μmol•L^－1)
Compd.	NCI-H460	HeLa	MGC-803
4aA	27±0.13	34±0.15	37±0.55
4bA	19±0.12	32±0.17	26±0.62
4cA	>50	34±0.23	47±0.15
4dA	48±0.23	>50	>50
4eA	>50	>50	>50
4aB	49±0.27	32±0.17	>50
4bB	48±0.35	33±0.23	40±0.18
4cB	44±0.15	38±0.31	>50
4dB	>50	>50	43±0.53
4eB	>50	>50	>50
4aC	46±0.23	>50	38±0.21
4bC	30±0.12	38±0.17	42±0.13
4cC	>50	>50	>50
4dC	>50	>50	>50
4eC	>50	>50	>50
4aD	>50	28±0.36	43±0.31
4bD	46±0.21	21±0.15	32±0.33
4cD	>50	>50	>50
4dD	>50	>50	>50
4eD	>50	>50	>50
4aE	>50	>50	48±0.02
4bE	41±0.11	30±0.24	>50
4cE	>50	>50	>50
4dE	>50	>50	>50
4eE	>50	>50	>50
4aF	>50	>50	>50
4bF	>50	>50	46±0.32
4cF	>50	>50	>50
4dF	>50	>50	>50
4eF	>50	>50	>50
CPT	1.6±0.025	6.4±0.087	2.3±0.058

Compd.	IC₅₀/(μmol•L^－1)
Compd.	NCI-H460	HeLa	MGC-803
4aA	27±0.13	34±0.15	37±0.55
4bA	19±0.12	32±0.17	26±0.62
4cA	>50	34±0.23	47±0.15
4dA	48±0.23	>50	>50
4eA	>50	>50	>50
4aB	49±0.27	32±0.17	>50
4bB	48±0.35	33±0.23	40±0.18
4cB	44±0.15	38±0.31	>50
4dB	>50	>50	43±0.53
4eB	>50	>50	>50
4aC	46±0.23	>50	38±0.21
4bC	30±0.12	38±0.17	42±0.13
4cC	>50	>50	>50
4dC	>50	>50	>50
4eC	>50	>50	>50
4aD	>50	28±0.36	43±0.31
4bD	46±0.21	21±0.15	32±0.33
4cD	>50	>50	>50
4dD	>50	>50	>50
4eD	>50	>50	>50
4aE	>50	>50	48±0.02
4bE	41±0.11	30±0.24	>50
4cE	>50	>50	>50
4dE	>50	>50	>50
4eE	>50	>50	>50
4aF	>50	>50	>50
4bF	>50	>50	46±0.32
4cF	>50	>50	>50
4dF	>50	>50	>50
4eF	>50	>50	>50
CPT	1.6±0.025	6.4±0.087	2.3±0.058