Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 55, Issue 8, Pages 2728-2732Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201510079
Keywords
androgen receptor antagonists; cancer; drug resistance; natural products; NMR spectroscopy
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan [23102006]
- Grants-in-Aid for Scientific Research [23102006] Funding Source: KAKEN
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Prostate cancer is treated with androgen receptor (AR) antagonists but most patients experience disease progression after long-term treatment with these compounds. Therefore, new AR antagonists are required for patient follow-up treatment. In the course of screening for a new AR antagonist, we isolated the novel compounds antarlides A-E (1-5) from Streptomyces sp. BB47. Antarlides are mutually isomeric with respect to the double bond and have a 22-membered-ring macrocyclic structure. The full stereostructure of 1 was established by chemical modifications, including methanolysis, the Trost method, acetonide formation, and the PGME method. 1-5 inhibited the binding of androgen to ARs in vitro. In addition, 2 inhibited the transcriptional activity of not only wild-type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists. Therefore, antarlides are a potent new generation of AR antagonists that overcome resistance.
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