Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer

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 sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate Cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in Anticancer activity across the four PC cell lines with IC₅₀ = 9.09 - 31.11 µM compared to the positive controls: bicalutamide (IC₅₀ = 45.20 -51.61 µM) and enzalutamide (IC₅₀ = 11.47 - 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15-30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH₂) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.

Androgen receptor (AR); Bicalutamide; Diarylpropionamide; Diastereoisomer; Diastereotopic; Oxidation; Prostate cancer (PC); Sulfoxide.