Preliminary investigations into triazole derived androgen receptor antagonists

Jarrad M. Altimari, Birunthi Niranjan, Gail P. Risbridger, Stephanie S. Schweiker, Anna E. Lohning, Luke C. Henderson

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

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 3 h. 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.

Original languageEnglish
Pages (from-to)2692-2706
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number9
DOIs
Publication statusPublished - 1 May 2014

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Androgen Receptor Antagonists
Androgen Antagonists
Triazoles
Ligands
Docks
Androgen Receptors
Bioactivity
Amides
Computer Simulation
Androgens
Inhibitory Concentration 50
Screening
Molecules

Cite this

Altimari, Jarrad M. ; Niranjan, Birunthi ; Risbridger, Gail P. ; Schweiker, Stephanie S. ; Lohning, Anna E. ; Henderson, Luke C. / Preliminary investigations into triazole derived androgen receptor antagonists. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 9. pp. 2692-2706.
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Preliminary investigations into triazole derived androgen receptor antagonists. / Altimari, Jarrad M.; Niranjan, Birunthi; Risbridger, Gail P.; Schweiker, Stephanie S.; Lohning, Anna E.; Henderson, Luke C.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 9, 01.05.2014, p. 2692-2706.

Research output: Contribution to journalArticleResearchpeer-review

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