Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide

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Abstract

A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34–45 μM and 29–151 μM, respectively. The data suggest that the latter compounds may be an excellent starting point for the development of prostate cancer therapeutics for both androgen dependent and independent forms of this disease. Docking of these compounds (each enantiomer) in silico into the T877A mutated androgen receptor, as possessed by LNCaP cells, was also undertaken.

Graphical abstract

Taking inspiration from the current leading antiandrogen used to treat prostate cancer, Bicalutamide (Casodex®), six triazole-derived analogues were synthesised and evaluated as androgen receptor (AR) antagonists. The synthesis for these compounds is very efficient, being five steps long and giving overall yields up to 85%. Docking of these compounds into the human AR (T877A mutant) showed encouraging interactions with the receptor and a comparison to established AR antagonists is presented. Evaluation of these compounds in vitro against hormone sensitive (LNCaP) and hormone independent (PC3) cells showed promising IC50 values of down to 34 μM and 29 μM, respectively.

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Acknowledgments

The authors gratefully acknowledge the CASS Foundation, Strategic Research Center for Chemistry and Biotechnology, the Faculty of Science Engineering and Built Environment, and the School of Life and Environmental Sciences for the funding to carry out this work. We thank Metabolomics Australia for the use of their HRMS service. We would also like to thank the Australian Government for an APA scholarship to J.A.

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