Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents

  • Eur J Med Chem. 2018 Jan 1:143:1325-1344. doi: 10.1016/j.ejmech.2017.10.031.
Xi Xu  1 ,  Raoling Ge  1 ,  Lei Li  1 ,  Jubo Wang  1 ,  Xiaoyu Lu  2 ,  Siqi Xue  2 ,  Xijing Chen  2 ,  Zhiyu Li  3 ,  Jinlei Bian  1
Affiliations
  • 1. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2. School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 3. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
PMID: 29117897 DOI: 10.1016/j.ejmech.2017.10.031
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.

Keywords
Androgen receptor; Antagonist; Prostate cancer; Tetrahydroisoquinoline thiohydantoin derivatives.