title: Antarlides: A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR-Targeted Therapy.
abstract: 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.
authors.affiliation: Bioscience and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Saito
authors.affiliation: Bioscience and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fujimaki
authors.affiliation: Biotechnology, Mahidol University, Bangkok, 10400, Thailand.
authors.forename: Watanalai
authors.initials: W
authors.lastname: Panbangred
authors.affiliation: Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan. yas@pu-toyama.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Igarashi
authors.affiliation: Bioscience and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan. imoto@bio.keio.ac.jp.
authors.forename: Masaya
authors.initials: M
authors.lastname: Imoto
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy*
chemical_list: D000726:Androgen Antagonists
keywords: NMR spectroscopy; androgen receptor antagonists; cancer; drug resistance; natural products