Novel bivalent securinine mimetics as topoisomerase I inhibitors
Novel bivalent securinine mimetics as topoisomerase I inhibitors
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作为拓扑异构酶 I 抑制剂的新型二价叶秋碱模拟物
DOI：
10.1039/c6md00563b
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发表时间：
2017-02-01
期刊：
影响因子：
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通讯作者：
Chen, Wei-Min
中科院分区：
文献类型：
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作者：
Hou, Wen;Lin, Hui;Chen, Wei-Min
合成了一系列含有不同连接C-15和C-15'的新型二价securinine模拟物，并评价了它们的拓扑异构酶I （Topo I）抑制活性。结果表明，含有刚性m取代苯连接剂的模拟R2具有三倍于亲本安全氨酸的Topo I抑制活性。综合构效关系分析与对接研究相结合，对这些二价模拟物的有效活性进行了合理化分析。机制研究证实了对接研究得出的结论，即活性二价模拟物不仅抑制Topo I和DNA之间的络合，而且还稳定了Topo I-DNA复合物本身。
A series of novel bivalent securinine mimetics incorporating different linkers between C-15 and C-15' were synthesized and their topoisomerase I (Topo I) inhibitory activities evaluated. It was thus revealed that mimetic R2 incorporating a rigid m-substituted benzene linker exhibits Topo I inhibitory activity three times that of parent securinine. Comprehensive structure-activity relationship analyses in combination with docking studies were used to rationalize the potent activity of these bivalent mimetics. Mechanistic studies served to confirm the deductions arising from docking studies that the active bivalent mimetics not only inhibited complexation between Topo I and DNA but also stabilized the Topo I-DNA complex itself.