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Novel bivalent securinine mimetics as topoisomerase I inhibitors.

ABSTRACT: 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.

SUBMITTER: Hou W

PROVIDER: S-EPMC6072210 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Novel bivalent securinine mimetics as topoisomerase I inhibitors.

Hou Wen W Lin Hui H Wang Zhen-Ya ZY Banwell Martin G MG Zeng Ting T Sun Ping-Hua PH Lin Jing J Chen Wei-Min WM

MedChemComm 20170103 2

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 <b>R2</b> incorporating a rigid <i>m</i>-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 ...[more]

PMID: 30108747

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