Design, chemical synthesis and biological evaluation of 3-spiromorpholinone/3-spirocarbamate androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3. Issue 17 (1st September 2015)

• Record Type: Journal Article
• Authors: Djigoué, Guy Bertrand; Kenmogne, Lucie Carolle; Roy, Jenny; Maltais, René; Poirier, Donald
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 17(2015)
• Page Start: 5433
• Page End: 5451
• Publication Date: 2015-09-01
• Subjects: ADT androsterone -- AR androgen receptor -- Ar aryl group -- DBD DNA binding domain -- DCM dichloromethane -- DHT dihydrotestosterone -- DIPEA N, N-diisopropylethylamine -- DMF dimethylformamide -- DMSO dimethylsulfoxide -- Δ4-dione 4-androstene-3, 17-dione -- EtOAc ethyl acetate -- FBS fetal bovine serum -- 17β-HSD 17β-hydroxysteroid dehydrogenase -- IR infrared spectroscopy -- KOt-Bu potassium tert-butylate -- LDA lithium diisopropylamide -- LR-MS low-resolution mass spectrometry -- NADPH nicotinamide adenosine dinucleotide phosphate reduced form -- NaHMDS sodium bis(trimethylsilyl)amide -- NaOMe sodium methoxide -- NMO N-methylmorpholine N-oxide -- NMR nuclear magnetic resonance -- Pd(dppf)Cl2 1, 1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride -- Ph phenyl group -- Rf Retardation or retention factor -- RT room temperature -- SAR structure–activity relationship -- TLC thin-layer chromatography -- p-TSA para-toluene sulfonic acid -- T testosterone -- TEA triethylamine -- THF tetrahydrofurane -- TPAP tetrapropylamonium perruthenate; Enzyme inhibitor -- Androgen -- Spiromorpholinone -- Chemical synthesis -- Prostate cancer -- 17β-Hydroxysteroid dehydrogenase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.07.049
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a key enzyme involved in the biosynthesis of testosterone and dihydrotestosterone. These hormones are known to stimulate androgen-dependent prostate cancer. In order to generate effective inhibitors of androgen biosynthesis without androgenic effect, we synthesized a new family of 3-spiromorpholinone and 3-spirocarbamate androsterone derivatives bearing diversified hydrophobic groups. We also tested their inhibitory activity in a microsomal fraction of 17β-HSD3-containing rat testes, and their androgenic effect on androgen-sensitive LAPC-4 cells. From our first structure–activity relationship (SAR) study, we noted that compound7e inhibited 17β-HSD3 (77% at 0.1 μM) compared to our reference compound RM-532-105 (76% at 0.1 μM), but exhibited a residual androgenic effect. A library of7e analogue compounds was next synthesized in order to generate compounds with reduced androgenic activity. In this new SAR study, the sulfonamide compound7e21 and the carboxamide compound7e22 inhibited 17β-HSD3 (IC50 = 28 and 88 nM, respectively). These two compounds were not androgenic and not cytotoxic even at the highest concentration tested, but their inhibitory activity decreased in intact LNCaP cells overexpressing 17β-HSD3 (LNCaP[17β-HSD3]). Structural modifications of these two lead compounds could however be tested to produce a second generation of 17β-HSD3 inhibitors.