Synthesis and Biological Evaluation of Bicalutamide Analogues for the Potential Treatment of Prostate Cancer

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.

Keywords: androgen receptor (AR); bicalutamide; diarylpropionamide; prostate cancer (PC); sulfone.

Figure 1

Chemical structures of the nonsteroidal antiandrogens (NSAA); flutamide, hydroxyflutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, and darolutamide.

Figure 2

Chemical structure of bicalutamide and the areas of structural modifications, ring (A), ring (B), and the linker area (C).

Scheme 1

Reagents and conditions, (i) DMA, rt, 3 h; (ii) H₂O₂, TFAA, DCM, rt, 24 h; (iii) NaH, THF, RT, 24 h.

Scheme 2

Reagents and conditions, (i) DMA, rt, 3 h; (ii) NaH, THF, RT, 24 h.

Scheme 3

Reagents and conditions, (i) mCPBA (2 equiv), DCM, rt, 24 h.

Figure 3

Dose response curves of sulfide compounds 16 (A) and 17 (C) compared to their corresponding sulfone derivatives 21 (B) and 22 (D), respectively, in the Oncotest monolayer assay of 22Rv1 (red), DU-145 (green), LnCaP (blue), and VCap (yellow) cell lines.

Figure 4

The predicted binding mode of compounds 16 (A) and 21 (B) within the hAR-LBD showing H-bond interactions (blue dashed line) with Arg 752, Gln 711, Met 742.

Scheme 4

Reagents and conditions, (i) MeONa/MeOH, toluene, 60 °C, 3 h, then NaOH 10%; (ii) Ac₂O, toluene, rt, 24 h; (iii) SOCl₂, DMAP, toluene; (iv) mCPBA (1 equiv), DCM, 0 °C, 15–30 min; (v) mCPBA (2 equiv), DCM, rt, 24 h.

Figure 5

The predicted binding mode of compound 27 (A) and bicalutamide (B) inside the hAR-LBD showing H-bond interactions (turquoise dashed line) with key amino acids, Arg 752, Gln 711, Met 742, and Thr 877.