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

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 21; pp. 4948 - 4953
• Main Authors: Altimari, Jarrad M., Niranjan, Birunthi, Risbridger, Gail P., Schweiker, Stephanie S., Lohning, Anna E., Henderson, Luke C.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2014; Elsevier
• Subjects: Androgen Antagonists - chemistry; Androgen Antagonists - pharmacology; Androgen receptor; Androgen Receptor Antagonists - chemical synthesis; Androgen Receptor Antagonists - pharmacology; Anilides - chemistry; Anilides - pharmacology; Bicalutamide; Cell Survival - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Click chemistry; Humans; Life Sciences & Biomedicine; Male; Molecular modeling; Nitriles - chemistry; Nitriles - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Receptors, Androgen - chemistry; Receptors, Androgen - metabolism; Science & Technology; Tosyl Compounds - chemistry; Tosyl Compounds - pharmacology; Triazole; Triazoles - chemistry; Tumor Cells, Cultured; Triazole; Bicalutamide; Click chemistry; Prostate cancer; Molecular modeling; Androgen receptor; DESIGN; ACID; REPLACEMENT; IMPACT; POTENT; METABOLISM; BIOLOGICAL EVALUATION; DERIVATIVES; BINDING
• DOI: 10.1016/j.bmcl.2014.09.036
• ISSN: 0960-894X

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 34μM and 29μM, respectively. [Display omitted] 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 34–45μM and 29–151μM, 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.