title: 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.affiliation: Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, Maryland 21201-1559, USA.
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.forename: Abhijit M
authors.initials: AM
authors.lastname: Godbole
authors.forename: Lalji K
authors.initials: LK
authors.lastname: Gediya
authors.forename: Marlena S
authors.initials: MS
authors.lastname: Martin
authors.forename: Tadas S
authors.initials: TS
authors.lastname: Vasaitis
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Kwegyir-Afful
authors.forename: Senthilmurugan
authors.initials: S
authors.lastname: Ramalingam
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Ates-Alagoz
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000730:Androstadienes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059748:Proteolysis / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000730:Androstadienes; D001562:Benzimidazoles; D011944:Receptors, Androgen; D013254:Steroid 17-alpha-Hydroxylase; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene