2. Academic Validation
  3. 6,6'-Dihydroxythiobinupharidine as a poison of human type II topoisomerases

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

  • Bioorg Med Chem Lett. 2019 Aug 1;29(15):1881-1885. doi: 10.1016/j.bmcl.2019.06.003.
Esha D Dalvie 1,  Jacob Gopas 2,  Avi Golan-Goldhirsh 3,  Neil Osheroff 4
Affiliations

Affiliations

  • 1 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
  • 2 Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Department of Oncology, Soroka University Medical Center, Beer Sheva 84105, Israel.
  • 3 The Jacob Blaustein Institutes for Desert Research, French Associates Institute for Agriculture and Biotechnology of Drylands, Ben-Gurion University of the Negev, Sede Boqer Campus, Beer Sheva 84990, Israel.
  • 4 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA; Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA. Electronic address: [email protected].
PMID: 31182315 DOI: 10.1016/j.bmcl.2019.06.003
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 Nuphar 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.

Keywords

6,6’-Dihydroxythiobinupharidine; Covalent poison; DNA cleavage; Topoisomerase IIα; Topoisomerase IIβ.

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