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6,6’-Dihydroxythiobinupharidine as a poison of human type II topoisomerases

Authors :
Esha D. Dalvie
Jacob Gopas
Avi Golan-Goldhirsh
Neil Osheroff
Source :
Bioorg Med Chem Lett
Publication Year :
2019
Publisher :
Elsevier BV, 2019.

Abstract

A number of natural products with medicinal properties increase DNA cleavage mediated by type II topoisomerases. In an effort to identify additional natural compounds that affect the activity of human type II topoisomerases, a blind screen of a library of 341 Mediterranean plant extracts was conducted. Extracts from Nuphcir lutea, the yellow water lily, were identified in this screen. N. lutea has been used in traditional medicine by a variety of indigenous populations. The active compound in N. lutea, 6,6’-dihydroxythiobinupharidine, was found to enhance DNA cleavage mediated by human topoisomerase IIα and IIβ ~8-fold and ~3-fold, respectively. Mechanistic studies with topoisomerase IIα indicate that 6,6’-dihydroxythiobinupharidine is a “covalent poison” that acts by adducting the enzyme outside of the DNA cleavage-ligation active site and requires the N-terminal domain of the protein for its activity. Results suggest that some of the medicinal properties of N. lutea may result from the interactions between 6,6’-dihydroxythiobinupharidine and the human type II enzymes.

Details

ISSN :
0960894X
Volume :
29
Database :
OpenAIRE
Journal :
Bioorganic & Medicinal Chemistry Letters
Accession number :
edsair.doi.dedup.....f3e0af53b69f7d2c8a7b6e33a763c45a
Full Text :
https://doi.org/10.1016/j.bmcl.2019.06.003