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Novel bivalent securinine mimetics as topoisomerase I inhibitors

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 inhibitor...

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Autores principales: Hou, Wen, Lin, Hui, Wang, Zhen-Ya, Banwell, Martin G., Zeng, Ting, Sun, Ping-Hua, Lin, Jing, Chen, Wei-Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072210/
https://www.ncbi.nlm.nih.gov/pubmed/30108747
http://dx.doi.org/10.1039/c6md00563b
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author Hou, Wen
Lin, Hui
Wang, Zhen-Ya
Banwell, Martin G.
Zeng, Ting
Sun, Ping-Hua
Lin, Jing
Chen, Wei-Min
author_facet Hou, Wen
Lin, Hui
Wang, Zhen-Ya
Banwell, Martin G.
Zeng, Ting
Sun, Ping-Hua
Lin, Jing
Chen, Wei-Min
author_sort Hou, Wen
collection PubMed
description 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.
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spelling pubmed-60722102018-08-14 Novel bivalent securinine mimetics as topoisomerase I inhibitors Hou, Wen Lin, Hui Wang, Zhen-Ya Banwell, Martin G. Zeng, Ting Sun, Ping-Hua Lin, Jing Chen, Wei-Min Medchemcomm Chemistry 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. Royal Society of Chemistry 2017-01-03 /pmc/articles/PMC6072210/ /pubmed/30108747 http://dx.doi.org/10.1039/c6md00563b Text en This journal is © The Royal Society of Chemistry 2017 http://creativecommons.org/licenses/by/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0)
spellingShingle Chemistry
Hou, Wen
Lin, Hui
Wang, Zhen-Ya
Banwell, Martin G.
Zeng, Ting
Sun, Ping-Hua
Lin, Jing
Chen, Wei-Min
Novel bivalent securinine mimetics as topoisomerase I inhibitors
title Novel bivalent securinine mimetics as topoisomerase I inhibitors
title_full Novel bivalent securinine mimetics as topoisomerase I inhibitors
title_fullStr Novel bivalent securinine mimetics as topoisomerase I inhibitors
title_full_unstemmed Novel bivalent securinine mimetics as topoisomerase I inhibitors
title_short Novel bivalent securinine mimetics as topoisomerase I inhibitors
title_sort novel bivalent securinine mimetics as topoisomerase i inhibitors
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072210/
https://www.ncbi.nlm.nih.gov/pubmed/30108747
http://dx.doi.org/10.1039/c6md00563b
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