Tyrosyl-DNA Phosphodiesterase 1 Inhibitor from an Anamorphic Fungus

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an enzyme that catalyzes hydrolysis of 3′-phosphotyrosyl bonds and is involved in repair of irreversible topoisomerase I (Top1)–DNA covalent complexes. Tdp1 inhibitors are regarded as potential cancer therapeutics in combination with Top1 inhibitors, which a...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2012-04, Vol.75 (4), p.764-767
Main Authors: Takagi, Motoki, Ueda, Jun-ya, Hwang, Ji-Hwan, Hashimoto, Junko, Izumikawa, Miho, Murakami, Hideki, Sekido, Yoshitaka, Shin-ya, Kazuo
Format: Article
Language:English
Subjects:
Animals
Drug Screening Assays, Antitumor
Fungi - chemistry
Humans
Mice
Molecular Structure
Phosphoric Diester Hydrolases - drug effects
Sesquiterpenes - chemistry
Sesquiterpenes - isolation & purification
Sesquiterpenes - pharmacology
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Summary:Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an enzyme that catalyzes hydrolysis of 3′-phosphotyrosyl bonds and is involved in repair of irreversible topoisomerase I (Top1)–DNA covalent complexes. Tdp1 inhibitors are regarded as potential cancer therapeutics in combination with Top1 inhibitors, which are currently used to treat human cancers. While screening for Tdp1 inhibitors, we discovered a novel compound, JBIR-21 (1), from the culture of an anamorphic fungus, RF-13305. The structure of 1 was established by extensive NMR and MS analyses. Compound 1 showed inhibitory activity against Tdp1 (IC50 value, 18 μM) and cytotoxic activity against cancer cell lines (IC50 values, 3.5–13 μM). Compound 1 also exhibited antitumor activity in a mouse xenograft model without adverse effects.
ISSN:0163-3864
1520-6025
DOI:10.1021/np2007389