title: Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide.
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.
authors.affiliation: Strategic Research Center for Chemistry and Biotechnology, Deakin University, Pigdons Road, Waurn Ponds Campus, Geelong 3216, Victoria, Australia; Institute for Frontier Materials, Deakin University, Pigdons Road, Waurn Ponds Campus, Geelong 3216, Victoria, Australia.
authors.forename: Jarrad M
authors.initials: JM
authors.lastname: Altimari
authors.affiliation: Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia.
authors.forename: Birunthi
authors.initials: B
authors.lastname: Niranjan
authors.affiliation: Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: Faculty of Health Sciences and Medicine, Bond University, Gold Coast 4229, Queensland, Australia.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Schweiker
authors.affiliation: Faculty of Health Sciences and Medicine, Bond University, Gold Coast 4229, Queensland, Australia.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Lohning
authors.affiliation: Strategic Research Center for Chemistry and Biotechnology, Deakin University, Pigdons Road, Waurn Ponds Campus, Geelong 3216, Victoria, Australia; Institute for Frontier Materials, Deakin University, Pigdons Road, Waurn Ponds Campus, Geelong 3216, Victoria, Australia. Electronic address: luke.henderson@deakin.edu.au.
authors.forename: Luke C
authors.initials: LC
authors.lastname: Henderson
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry* / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000813:Anilides / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D014105:Tosyl Compounds / Q000737:chemistry* / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D014230:Triazoles; C053541:bicalutamide
keywords: Androgen receptor; Bicalutamide; Click chemistry; Molecular modeling; Prostate cancer; Triazole