Antarlides F-H, new members of the antarlide family produced by Streptomyces sp. BB47.
Castration-resistant prostate cancer (CRPC) is the most aggressive form of this disease. CRPC remains dependent on androgen receptor (AR) signaling. Therefore, a novel AR antagonist, enzalutamide, is used clinically for the treatment of men with metastatic CRPC. However, enzalutamide-resistant AR has appeared, and a new type of AR antagonist is desired. Previously, in the course of screening for a new type of AR antagonist, we isolated a series of compounds, designated antarlides A-E, that share a novel 22-membered-ring macrocyclic structure and are produced by Streptomyces sp. BB47. In the present study, we found that this strain also produces antarlides F-H as minor components. Antarlide F is a novel geometric isomer of known antarlides. On the other hand, antarlides G and H are new members of the antarlide family that have a 20-membered-ring macrocyclic structure. Antarlides G and H inhibited the binding of androgen to AR in vitro at concentrations similar to those observed with antarlides A-E. In addition, antarlide G inhibited the transcriptional activity of not only wild-type AR but also enzalutamide-resistant AR, suggesting that antarlides with either 22- or 20-membered rings may serve as potent third-generation AR antagonists capable of overcoming resistance to enzalutamide.
Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, Kanagawa, Japan.
Shun
S
Saito
Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, Kanagawa, Japan.
Takahiro
T
Fujimaki
Department of Biotechnology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Watanalai
W
Panbangred
Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.
Ryuichi
R
Sawa
Biotechnology Research Center, Toyama Prefectural University, Toyama, Japan.
Yasuhiro
Y
Igarashi
Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, Kanagawa, Japan.
Masaya
M
Imoto
D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy; D013302:Streptomyces / Q000378:metabolism*
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D047028:Macrocyclic Compounds; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide