Abstract
One of the main directions of steroid research is the preparation of modified derivatives in which, in addition to changes in physicochemical properties, receptor binding is significantly altered, thus a bioactivity different from that of the parent compound predominates. In the frame of this work, 2-arylidene derivatives were first synthesized by regioselective modification of the A-ring of natural sex hormone, 5α-dihydrotestosterone (DHT). After Claisen-Schmidt condensations of DHT with (hetero)aromatic aldehydes in alkaline EtOH, heterocyclizations of the α,β-enones were performed with 3-amino-1,2,4-triazole, 3-aminopyrazole and 3-amino-5-methylpyrazole in the presence of t-BuOK in DMF to afford 7′-epimeric mixtures of A-ring-fused azolo-dihydropyrimidines, respectively. Depending on the electronic demand of the substituents of the arylidene moiety, spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the heteroring led to triazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines in good yields, while, using the Jones reagent as a strong oxidant, 17-oxidation also occurred. The crystal structures of an arylidene and a triazolopyrimidine product have been determined by single crystal X-ray diffraction and both were found to crystallize in the monoclinic crystal system at P21 space group. Most derivatives were found to diminish the transcriptional activity of androgen receptor (AR) in reporter cell line. The candidate compound (17β-hydroxy-2-(4-chloro)benzylidene-5α-androstan-3-one, 2f) showed to suppress androgen-mediated AR transactivation in a dose-dependent manner. We confirmed the cellular interaction of 2f with AR, described the binding in AR-binding cavity by the flexible docking and showed the ability of the compound to suppress the expression of AR-regulated genes in two prostate cancer cell lines.
Highlights
The androgen receptor (AR) is a ligand-activated transcription factor that belongs to the superfamily of steroid and thyroid hormone receptors and plays a crucial role in the normal development of male reproductive tissues
Un the disease rapidly progresses to castration-resistant pros tate cancer (CRPC) stage, which is defined by AR-pathway alterations including AR gene amplification, overexpression, mutation, splice var iants, and the increase in adrenal and intratumoral androgens
A-ring-fused pyrazolo[1,5-a]pyrimidine and triazolo[1,5-a]pyrimi dine derivatives of DHT were efficiently prepared in two steps
Summary
The androgen receptor (AR) is a ligand-activated transcription factor that belongs to the superfamily of steroid and thyroid hormone receptors and plays a crucial role in the normal development of male reproductive tissues. Mostly modified in the D-ring of the androstane core have been investigated as AR modulators or for their anti-PCa properties [6,7,8,9,10,11], but only galeterone [12] and abiraterone [13] (Fig. 1) have entered clinical trials. Both agents showed to target adrenal and tumour androgen production by inhibition of the ste roidogenic enzyme CYP17A1, and galeterone is capable to induce AR and AR-V7 degradation in PCa by competitive antagonism of AR [14]. Interaction within the AR’s cavity was performed by the flexible docking
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