Abstract
The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of 15 bicalutamide analogues (sulfide, deshydroxy, sulfone, and O-acetylated) were prepared and their antiproliferative activity evaluated against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP, and VCap). Bicalutamide and enzalutamide were used as positive controls. Seven of these compounds displayed remarkable enhancement in anticancer activity across the four PC cell lines. The deshydroxy analogue (16) was the most active compound with IC50 = 6.59–10.86 µM. Molecular modeling offers a plausible explanation of the higher activity of the sulfide analogues compared to their sulfone counterparts.
Highlights
We present the design and synthesis of a series of new bicalutamide analogues, building on our previous work [10,11,12,13] to offer new therapeutic options for combating the resistance observed in the clinical use of androgen receptor (AR) antagonists
Fifteen bicalutamide derivatives were prepared and their antiproliferative activity was evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP, and VCap). These modifications offer an insight into the SAR of various propionanilide analogues
Molecular modeling was used to find a plausible explanation of the drop in activity upon oxidation of the sulfide analogue (16) into sulfone counterpart (21)
Summary
The first generation NSAAs include flutamide, hydroxyflutamide, and bicalutamide (Figure 1) These antiandrogens eventually fail to inhibit the AR upon long-term treatment, switching from being AR antagonists to AR agonists with the development of castration-resistant prostate cancer (CRPC), an aggressive form of the disease with poor prognosis. An in silico docking study was performed to compare the putative binding modes of the sulfide (S) compound 16 (IC50 = 6.59–10.86 μM) and its sulfone (SO2) analogue 21 (IC50 = 24.64–43.04 μM) Both compounds share key interactions including an H-bond between Molecules 2021, 26, x. TThhee pprreeddiicctteedd bbiinnddiinngg mmooddee ooff ccoommppoouunnddss 1166 ((AA)) aanndd 2211 ((BB))wwiitthhiinn tthheehhAARR--LLBBDD sshhoowwiinngg HH--bboonndd iinntteerraaccttiioonnss ((bblluuee ddaasshheeeddd lliinnneee))) wwwiiittthhh AAArrrggg 777555222,,,GGGlllnnn777111111,,,MMMeeettt777444222.
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