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6,6’-Dihydroxythiobinupharidine as a poison of human type II topoisomerases
- 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.
- Subjects :
- Topoisomerase iiα
Clinical Biochemistry
Pharmaceutical Science
Human type
01 natural sciences
Biochemistry
Poisons
Article
chemistry.chemical_compound
Alkaloids
Dna cleavage
Drug Discovery
Humans
Nuphar lutea
Molecular Biology
chemistry.chemical_classification
biology
Plant Extracts
010405 organic chemistry
Topoisomerase
Organic Chemistry
Active site
biology.organism_classification
0104 chemical sciences
010404 medicinal & biomolecular chemistry
DNA Topoisomerases, Type II
Enzyme
chemistry
biology.protein
Molecular Medicine
DNA
Subjects
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