Synthesis and biological evaluation of naphthoquinone-coumarin conjugates as topoisomerase II inhibitors

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• 作者：Idaira Hueso-Falc&oacute ; n^a ; Á ; ngel Amesty^a ; ¹ ; Laura Anaissi-Afonso^b ; ¹ ; Isabel Lorenzo-Castrillejo^b ; Fé ; lix Machí ; n^b ; ^{fmachin@funcanis.org} ; Ana Esté ; vez-Braun^a ; ^{aestebra@ull.es}
• 关键词：2-Hydroxynaphthoquinone ; 4-Hydroxycoumarin ; Privileged structures ; Topoisomerase II ; ATPase ; Docking
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：484-489
• 全文大小：1275 K
• 卷排序：27

文摘

Based on previous Topoisomerase II docking studies of naphthoquinone derivatives, a series of naphthoquinone-coumarin conjugates was synthesized through a multicomponent reaction from aromatic aldehydes, 4-hydroxycoumarin and 2-hydroxynaphthoquinone. The hybrid structures were evaluated against the α isoform of human topoisomerase II (hTopoIIα), Escherichia coli DNA Gyrase and E. coli Topoisomerase I. All tested compounds inhibited the hTopoIIα-mediated relaxation of negatively supercoiled circular DNA in the low micromolar range. This inhibition was specific since neither DNA Gyrase nor Topoisomerase I were affected. Cleavage assays pointed out that naphthoquinone-coumarins act by catalytically inhibiting hTopoIIα. ATPase assays and molecular docking studies further pointed out that the mode of action is related to the hTopoIIα ATP-binding site.