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.

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.

• Authors: Puranik Purushottamachar, Abhijit M Godbole, Lalji K Gediya, Marlena S Martin, Tadas S Vasaitis, Andrew K Kwegyir-Afful, Senthilmurugan Ramalingam, Zeynep Ates-Alagoz, Vincent C O Njar
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 12 Pg. 4880-98 (Jun 27 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23713567 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Androstadienes
• Benzimidazoles
• Receptors, Androgen
• Steroid 17-alpha-Hydroxylase
• 3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene

Topics

• Androstadienes (chemistry, pharmacology, therapeutic use)
• Benzimidazoles (chemistry, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Drug Design
• Humans
• Male
• Molecular Targeted Therapy
• Prostatic Neoplasms (drug therapy, pathology)
• Proteolysis (drug effects)
• Receptors, Androgen (genetics, metabolism)
• Steroid 17-alpha-Hydroxylase (antagonists & inhibitors)
• Transcriptional Activation (drug effects)