title: Preliminary investigations into triazole derived androgen receptor antagonists.
abstract: A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40 μM, the most promising three compounds were found to display IC50 values of 40-50 μM against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue.
authors.affiliation: Strategic Research Center for Chemistry and Biotechnology, 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 and 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 and 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: D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D009154:Mutation; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D014230:Triazoles
keywords: Androgen receptor; Click chemistry; Molecular modelling; Prostate cancer; Triazole