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Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives Containing Benzoic Acid Group as Potential AKR1C3 Inhibitors
Author(s) -
Sun Mingjiao,
Zhou Yi,
Zhuo Xuefang,
Wang Sheng,
Jiang Shisheng,
Peng Zhihuan,
Kang Ke,
Zheng Xuehua,
Sun Mingna
Publication year - 2020
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.202000519
Subject(s) - chemistry , benzamide , indole test , benzoic acid , sulfanyl , cytotoxicity , prostate cancer , stereochemistry , enzyme , dihydrotestosterone , pharmacology , biochemistry , androgen , cancer , in vitro , medicine , biology , hormone
Castration‐resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer, characterized by reactivation of the androgen axis. Aldo‐keto reductase 1C3 (AKR1C3) converts androstenedione (AD) and 5α‐androstanedione to testosterone (T) and 5α‐dihydrotestosterone (DHT), respectively. In CRPC, AKR1C3 is upregulated and implicated in drug resistance and has been regarded as a potential therapeutic target. Here we examined a series of indole derivatives containing benzoic acid or phenylhydroxamic acid and found that 4‐({3‐[(3,4,5‐trimethoxyphenyl)sulfanyl]‐1 H ‐indol‐1‐yl}methyl)benzoic acid ( 3e ) and N ‐hydroxy‐4‐({3‐[(3,4,5‐trimethoxyphenyl)sulfanyl]‐1 H ‐indol‐1‐yl}methyl)benzamide ( 3q ) inhibited 22Rv1 cell proliferation with IC 50 values of 6.37 μ M and 2.72 μ M , respectively. In enzymatic assay, compounds 3e and 3q exhibited potent inhibitory effect against AKR1C3 (IC 50 =0.26 and 2.39 μ M , respectively). These results indicated that compounds 3e and 3q might be useful leads for further investigation of more potential AKR1C3 inhibitors used for CRPC.