Synthesis of dihydrotestosterone derivatives modified in the A-ring with (hetero)arylidene, pyrazolo[1,5-a]pyrimidine and triazolo[1,5-a]pyrimidine moieties and their targeting of the androgen receptor in prostate cancer

One of the main directions steroid research is preparation modified derivatives in which, addition to changes physicochemical properties, receptor binding significantly altered, thus a bioactivity different from that parent compound predominates. In frame this work, 2-arylidene were first synthesized by regioselective modification A-ring natural sex hormone, 5α-dihydrotestosterone (DHT). After Claisen-Schmidt condensations DHT with (hetero)aromatic aldehydes alkaline EtOH, heterocyclizations α,β-enones performed 3-amino-1,2,4-triazole, 3-aminopyrazole and 3-amino-5-methylpyrazole presence t-BuOK DMF afford 7′-epimeric mixtures A-ring-fused azolo-dihydropyrimidines, respectively. Depending on electronic demand substituents arylidene moiety, spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation heteroring led triazolo[1,5-a]pyrimidines pyrazolo[1,5-a]pyrimidines good yields, while, using Jones reagent as strong oxidant, 17-oxidation also occurred. The crystal structures an triazolopyrimidine product have been determined single X-ray diffraction both found crystallize monoclinic system at P21 space group. Most diminish transcriptional activity androgen (AR) reporter cell line. candidate (17β-hydroxy-2-(4-chloro)benzylidene-5α-androstan-3-one, 2f) showed suppress androgen-mediated AR transactivation dose-dependent manner. We confirmed cellular interaction 2f AR, described AR-binding cavity flexible docking ability expression AR-regulated genes two prostate cancer lines.