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苯并恶嗪类作为新型人类拓扑异构酶 I 抑制剂和潜在毒物。

Benzoxazines as new human topoisomerase I inhibitors and potential poisons.

机构信息

Department of Biotechnology, Faculty of Science, Necmettin Erbakan University, Konya, Turkey.

Izmir International Biomedicine and Genome Institute, iBG-izmir, Dokuz Eylül University, Izmir, Turkey.

出版信息

Daru. 2020 Jun;28(1):65-73. doi: 10.1007/s40199-019-00315-x. Epub 2019 Dec 12.

Abstract

BACKGROUND

The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable.

OBJECTIVES

In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials.

METHODS

We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system.

RESULTS

While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC:8.34 mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC:0.0006 mM). BONC-013 was much more poisonous than camptothecin (IC:0.034 mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R position were play a role for increasing of its poisonous effect.

CONCLUSION

As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs. Graphical abstract.

摘要

背景

尽管拓扑异构酶 I 靶向药物在临床上用于治疗实体瘤,但市场上的此类药物数量非常有限。因此,寻找专门针对拓扑异构酶 I 的新化学结构的研究仍然引人注目。

目的

在本研究中,我们测试了之前合成的 3,4-二氢-2H-1,4-苯并恶嗪-3-酮衍生物,以揭示它们对人 DNA 拓扑异构酶 I 的抑制潜力。

方法

我们通过松弛测定法研究了 3,4-二氢-2H-1,4-苯并恶嗪-3-酮衍生物对人拓扑异构酶 I 的抑制活性,以阐明有效衍生物与 EMSA 和 T4 DNA 连接酶基于嵌入测定的抑制机制。通过 SAR 研究,试图找出环系统中的有效基团。

结果

虽然 10 种化合物表现出催化抑制活性,但有 8 种化合物被发现是潜在的拓扑异构酶毒物。其中 4 种化合物还具有这两种活性。2-羟基-3,4-二氢-2H-1,4-苯并恶嗪-3-酮(BONC-001)是最有效的催化抑制剂(IC:8.34 mM),乙基 6-氯-4-甲基-3-氧代-3,4-二氢-2H-1,4-苯并恶嗪-2-乙酸酯(BONC-013)是最强的潜在毒物(IC:0.0006 mM)。BONC-013 比喜树碱(IC:0.034 mM)更毒。嵌入测定表明,BONC-013 不是嵌入剂,BONC-001 很可能以未知的方式阻止酶-底物结合。本研究的另一个重要结果是,苯并恶嗪环 R 位上的 OH 基团而不是乙氧羰基甲基基团对于 hTopo I 催化抑制很重要,而 R 位上的 R1 位上的甲基基团的附加对于增加其毒性作用具有重要意义。

结论

因此,我们提出了新的 DNA 拓扑异构酶 I 抑制剂,它们可能为未来的抗癌药物设计提供新的结构。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8144/7214584/0771a1e0e436/40199_2019_315_Figa_HTML.jpg

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