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

Castrate-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)thio)-1 H -indol-1-yl)methyl)benzoic acid ( 3e ) and N-hydroxy-4-((3-((3,4,5-trimethoxyphenyl)thio)-1 H -indol-1-yl)methyl)benzamide ( 3q ) inhibited 22Rv1 cells proliferation with IC 50 value of 6.37 μm and 2.72 μm, respectively. In enzymatic assay, compounds 3e and 3q exhibited potent inhibitory effect against AKR1C3 (IC 50 = 0.26 and 2.39 μm, respectively). These results indicated that compounds 3e and 3q might be useful leads for further investigation of more potential AKR1C3 inhibitors used for CRPC.