TY - JOUR
T1 - 6,6’-Dihydroxythiobinupharidine as a poison of human type II topoisomerases
AU - Dalvie, Esha D.
AU - Gopas, Jacob
AU - Golan-Goldhirsh, Avi
AU - Osheroff, Neil
N1 - Funding Information:
The authors declare no competing financial interests. This research was supported by National Institutes of Health grant GM126363 (N.O.), and funding from ICA in Israel, the Deutsche Forschungsgemeinschaft , and the Richard H. Holzer Foundation (NJ, USA) (A.G.-G. and J.G.). We are grateful to Dr. Heather J. McCartney for her work on the initial screen, to Dr. Joseph E. Deweese for generously providing the catalytic core of human topoisomerase IIα, to Dr. Wolfgang Eisenreich for confirming the identity and purity of DTBN by NMR analyses, and to Dr. Elizabeth G. Gibson, Alexandria A. Oviatt, and Justin W. Lopez for critical reading of the manuscript.
Publisher Copyright:
© 2019
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - 6,6’-Dihydroxythiobinupharidine
KW - Covalent poison
KW - DNA cleavage
KW - Topoisomerase IIα
KW - Topoisomerase IIβ
UR - http://www.scopus.com/inward/record.url?scp=85066859522&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2019.06.003
DO - 10.1016/j.bmcl.2019.06.003
M3 - Article
C2 - 31182315
AN - SCOPUS:85066859522
SN - 0960-894X
VL - 29
SP - 1881
EP - 1885
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 15
ER -
