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 5αandrostanedione 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]-1H-indol-1-yl}methyl)benzoic acid (3e) and N-hydroxy-4-({3-[(3,4,5-trimethoxyphenyl)sulfanyl]-1H-indol-1-yl}methyl)benzamide (3q) inhibited 22Rv1 cell proliferation with IC 50 values 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.

Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis

“…The indole scaffold of indomethacin is also present in ASP9521 [ 46 ], a potent AKR1C3 inhibitor that was in a phase 1 clinical trial for CRPC (May 2011, NCT01352208, discontinued) and seems to be a crucial molecular moiety for establishing effective interactions with the active site of AKR1C3 [ 47 ]. With the aim of investigating whether the indole and benzimidazole moieties present in our studied compounds could provide the ability to inhibit the AKR1C3 enzyme resulting in synergistic multi-target properties, we tested compounds 3a – 3d and 4a – 4d on the recombinant purified AKR1C3 enzyme by measuring S-tetralol oxidation in the presence of NADP + ( Figure 6 ).…”

X-ray structure of human aldo–keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation, molecular docking and structural analysis

“…1 and Table 1). 26,27,30,31 Based on this in vitro enzymatic screen, compounds 1-4 and 8 were identified as potential inhibitors of AKR1C3 (Fig. 1 and Table 1).…”

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

“…Various natural polyphenols, such as flavonoids or alkaloids, have shown significant inhibitory activities against AKR1C enzymes [33][34][35]. Chalcones, as natural secondary metabolites that belong to the class of flavonoids, are largely distributed in the plant kingdom.…”