Synthesis of new derivatives of 21-imidazolyl-16-dehydropregnenolone as inhibitors of 5α-reductase 2 and with cytotoxic activity in cancer cells

• Published in: Bioorganic & medicinal chemistry 2017-03, Vol.25 (5), p.1600-1607
• Main Authors: Silva-Ortiz, Aylin Viviana, Bratoeff, Eugene, Ramírez-Apan, Teresa, Heuze, Yvonne, Soriano, Juan, Moreno, Isabel, Bravo, Marisol, Bautista, Lucero, Cabeza, Marisa
• Format: Article
• Language: English
• Subjects: 16-Dehydropregnenolone acetate derivatives; 5-alpha Reductase Inhibitors - pharmacology; 5-α-reductase; Alicyclic ester moiety at C-3 of the steroidal skeleton; Animals; Carbon-13 Magnetic Resonance Spectroscopy; Cell Line, Tumor; Cell lines: PC-3; Cholestenone 5 alpha-Reductase - drug effects; Cytotoxic activity; Humans; Mass Spectrometry; MCF7; Mice; Pregnenolone - analogs & derivatives; Pregnenolone - pharmacology; Proton Magnetic Resonance Spectroscopy; Rats; SK-LU-1
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.01.018

[Display omitted] •Ten novel 21-imidazolyl-16-dehydropregnenolone derivatives were synthesized.•These steroids have different ester moiety at C-3 to compare their activity.•Steroids with alicyclic ester at C-3 showed 5α-R2 inhibition and in vivo activity.•Only derivatives with an alicyclic ester at C-3 exhibited anticancer activity.•The ester moiety’s size matters for enzyme selectivity and anticancer activity. The aim of this study was to synthesize several 16-dehydropregnenolone derivatives containing an imidazole ring at C-21 and a different ester moiety at C-3 as inhibitors of 5α-reductase 1 and 2 isoenzymes. Their binding capacity to the androgen receptor (AR) was also studied. Additionally, we evaluated their pharmacological effect in a castrated hamster model and their cytotoxic activity on a panel of cancer cells (PC-3, MCF7, SK-LU-1). The results showed that only the derivatives with an alicyclic ester at C-3 showed 5α-R2 enzyme inhibition activity, the most potent of them being 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3β-yl-cyclohexanecarboxylate with an IC50 of 29nM. This is important because prostatic benign hyperplasia is directly associated with the presence of 5α-R2. However, all the derivatives failed to inhibit 5α-R1 or bind to the AR. These alicyclic ester derivatives decreased the weight and size of androgen-dependent glands in the hamster, indicating they are very active in vivo and are not toxic. In addition, the 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3β-yl-acetate derivative showed the highest cytotoxic activity on the three cancer cell lines studied. It is therefore important in the synthesis of steroidal compounds to consider the size of the ester moiety at C-3 of the steroid skeleton, which is key in obtaining biological activity, as observed in this experiment.