TY - JOUR
T1 - Antarlides
T2 - A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR-Targeted Therapy
AU - Saito, Shun
AU - Fujimaki, Takahiro
AU - Panbangred, Watanalai
AU - Igarashi, Yasuhiro
AU - Imoto, Masaya
N1 - Publisher Copyright:
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2016/2/18
Y1 - 2016/2/18
N2 - 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.
AB - 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.
KW - NMR spectroscopy
KW - androgen receptor antagonists
KW - cancer
KW - drug resistance
KW - natural products
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U2 - 10.1002/anie.201510079
DO - 10.1002/anie.201510079
M3 - Article
C2 - 26805525
AN - SCOPUS:84958729571
SN - 1433-7851
VL - 55
SP - 2728
EP - 2732
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 8
ER -
