Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.

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TitleSystematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.
Publication TypeJournal Article
Year of Publication2013
AuthorsPurushottamachar, P, Godbole, AM, Gediya, LK, Martin, MS, Vasaitis, TS, Kwegyir-Afful, AK, Ramalingam, S, Ates-Alagoz, Z, Njar, VCO
JournalJ Med Chem
Volume56
Issue12
Pagination4880-98
Date Published2013 Jun 27
ISSN1520-4804
KeywordsAndrostadienes, Benzimidazoles, Cell Line, Tumor, Cell Proliferation, Down-Regulation, Drug Design, Humans, Male, Molecular Targeted Therapy, Prostatic Neoplasms, Proteolysis, Receptors, Androgen, Steroid 17-alpha-Hydroxylase, Transcriptional Activation
Abstract

As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.

DOI10.1021/jm400048v
Alternate JournalJ. Med. Chem.
PubMed ID23713567
Grant List1R01CA129379-01 A2 / CA / NCI NIH HHS / United States
5R01CA129379-02 / CA / NCI NIH HHS / United States
R21 CA11791-01 / CA / NCI NIH HHS / United States