Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents
Abstract Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists. Highlights A series of tetrahydroisoquinoline thiohydantoin derivatives were synthesized and evaluated for its inhibition of cell growth in bicalutamide-resistant cells as well as AR nuclear translocation. The most potent compound 55 shows comparable ability with enzalutamide in proliferation inhibition of LNCaP cells and AR antagonistic activity. More importantly, 55 displays less cyctotoxic to AR-negative cells and good pharmacokinetic properties. Graphical abstract [DISPLAY OMISSION]
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