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

• Published in: Bioorganic & medicinal chemistry letters 2017-02, Vol.27 (3), p.484-489
• Main Authors: Hueso-Falcón, Idaira, Amesty, Ángel, Anaissi-Afonso, Laura, Lorenzo-Castrillejo, Isabel, Machín, Félix, Estévez-Braun, Ana
• Format: Article
• Language: English
• Subjects: 2-Hydroxynaphthoquinone; 4-Hydroxycoumarin; ATPase; Coumarins - chemistry; Coumarins - pharmacology; DNA Topoisomerases, Type II - metabolism; Docking; Dose-Response Relationship, Drug; Humans; Molecular Structure; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Privileged structures; Structure-Activity Relationship; Topoisomerase II; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.12.040

[Display omitted] 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.