Synthesis, Topo I Inhibition and Antitumor Evaluation of Aza-indenoisoquinoline Derivatives

doi:10.6023/cjoc202504029

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (8): 2815-2824.DOI: 10.6023/cjoc202504029 Previous Articles Next Articles

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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

郑彬, 韦敏, 林雯雯, 潘成学^*()

广西师范大学化学与药学学院省部共建药用资源化学与药物分子工程国家重点实验室广西桂林 541004

收稿日期:2025-04-27 修回日期:2025-06-13 发布日期:2025-08-18
基金资助:
国家自然科学基金(82160656); 国家自然科学基金(81960638)

Synthesis, Topo I Inhibition and Antitumor Evaluation of Aza-indenoisoquinoline Derivatives

Bin Zheng, Min Wei, Wenwen Lin, Chengxue Pan^*()

School of Chemistry and Pharmaceutical Sciences/State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, Guangxi 541004

Received:2025-04-27 Revised:2025-06-13 Published:2025-08-18
Contact: *E-mail:chengxuepan@163.com
Supported by:
Natural Science Foundation of China(82160656); Natural Science Foundation of China(81960638)

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Abstract

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

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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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References 25

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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

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

Synthesis, Topo I Inhibition and Antitumor Evaluation of Aza-indenoisoquinoline Derivatives

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