Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives Containing Benzoic Acid Group as Potential AKR1C3 Inhibitors

Abstract 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.