Design, chemical synthesis and biological evaluation of 3-spiromorpholinone/3-spirocarbamate androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3.
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 compound 7e 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 of 7e analogue compounds was next synthesized in order to generate compounds with reduced androgenic activity. In this new SAR study, the sulfonamide compound 7e21 and the carboxamide compound 7e22 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.
Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Laval UNiversity (Faculty of Medicine), 2705 Laurier Boulevard, Québec, QC G1V 4G2, Canada.
Guy Bertrand
GB
Djigoué
Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Laval UNiversity (Faculty of Medicine), 2705 Laurier Boulevard, Québec, QC G1V 4G2, Canada.
Lucie Carolle
LC
Kenmogne
Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Laval UNiversity (Faculty of Medicine), 2705 Laurier Boulevard, Québec, QC G1V 4G2, Canada.
Jenny
J
Roy
Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Laval UNiversity (Faculty of Medicine), 2705 Laurier Boulevard, Québec, QC G1V 4G2, Canada.
René
R
Maltais
Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Laval UNiversity (Faculty of Medicine), 2705 Laurier Boulevard, Québec, QC G1V 4G2, Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
Donald
D
Poirier
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000728:Androgens / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D009025:Morpholines / Q000737:chemistry* / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*
D000728:Androgens; D002219:Carbamates; D004791:Enzyme Inhibitors; D009025:Morpholines; D013141:Spiro Compounds; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3
17β-Hydroxysteroid dehydrogenase; Androgen; Chemical synthesis; Enzyme inhibitor; Prostate cancer; Spiromorpholinone