Design, synthesis and anti-tumor evaluation of novel thiohydantoin congeners as androgen receptor antagonists with in vivo study

Abstract

Novel thiohydantoin derivatives were designed as androgen antagonists based on the binding pattern of enzalutamide to the androgen receptor that avoided the bifurcated activation pattern of dihydrotestosterone. Twelve thiohydantoin derivatives were synthesized following Michael-type addition which were fully characterized. The dicyanide derivatives 3a showed the best LNCaP inhibition demonstrating IC50 of 2.64 µM with a potential to inhibit its S-phase reducing the natural DNA transactivation of androgens. Moreover, apoptosis initiation was observed in the early phase with 22.74 % in contrast to 9.06 % at the late phase with respect to 0.44 % and 0.13 % of the control cells at early and late stages, respectively. In vivo evaluation of 3a significantly ameliorated the testosterone-induced increase in the prostate index and weight as compared to finasteride. This was confirmed by the histopathological examinations of prostatic tissues that demonstrated a reduction in the accompanied histopathological changes as well as lowering the immunohistochemical up-regulation of androgen receptors induced by testosterone. Moreover, molecular docking simulation justified the achieved biological activity.