Preliminary investigations into triazole derived androgen receptor antagonists

Altimari,JM, Niranjan,B, Risbridger,GP, Schweiker,SS, Lohning,AE and Henderson,LC 2014, Preliminary investigations into triazole derived androgen receptor antagonists, Bioorganic and Medicinal Chemistry, vol. 22, no. 9, pp. 2692-2706, doi: 10.1016/j.bmc.2014.03.018.

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Title Preliminary investigations into triazole derived androgen receptor antagonists
Author(s) Altimari,JM
Henderson,LCORCID iD for Henderson,LC
Journal name Bioorganic and Medicinal Chemistry
Volume number 22
Issue number 9
Start page 2692
End page 2706
Total pages 15
Publisher Elsevier
Place of publication England, London
Publication date 2014-05
ISSN 1464-3391
Keyword(s) Androgen receptor
Click chemistry
Molecular modelling
Prostate cancer
Science & Technology
Life Sciences & Biomedicine
Physical Sciences
Biochemistry & Molecular Biology
Chemistry, Medicinal
Chemistry, Organic
Pharmacology & Pharmacy
Summary 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.
Language eng
DOI 10.1016/j.bmc.2014.03.018
Field of Research 030401 Biologically Active Molecules
030503 Organic Chemical Synthesis
Socio Economic Objective 970103 Expanding Knowledge in the Chemical Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, Elsevier
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