Synthesis of 5α-Androstane-17-spiro-δ-lactones with a 3-Keto,3-Hydroxy, 3-Spirocarbamate or 3-Spiromorpholinone as Inhibitors of 17β-Hydroxysteroid Dehydrogenases

Molecules

Guy Bertrand Djigoué¹  Béatrice Tchédam Ngatcha¹  Jenny Roy¹ 

[1]Laboratory of Medicinal Chemistry, CHU de Québec (CHUL) — Research Center and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Québec (Québec), G1V 4G2, Canada[2] height:6px

[3]"> ^†These authors contributed equally to this work.

关键词: synthesis;    steroids;    spirolactone;    enzyme inhibitor;    17β-hydroxysteroid dehydrogenase;   

DOI  :  10.3390/molecules18010914

来源: mdpi

【 摘 要 】

We synthesized two series of androstane derivatives as inhibitors of type 3 and type 5 17β-hydroxysteroid dehydrogenases (17β-HSDs). In the first series, four monospiro derivatives at position C17 were prepared from androsterone (ADT) or epi-ADT. After the protection of the alcohol at C3, the C17-ketone was alkylated with the lithium acetylide of tetrahydro-2-(but-3-ynyl)-2-H-pyran, the triple bond was hydrogenated, the protecting groups hydrolysed and the alcohols oxidized to give the corresponding 3-keto-17-spiro-lactone derivative. The other three compounds were generated from this keto-lactone by reducing the ketone at C3, or by introducing one or two methyl groups. In the second series, two dispiro derivatives at C3 and C17 were prepared from epi-ADT. After introducing a spiro-δ-lactone at C17 and an oxirane at C3, an aminolysis of the oxirane with L-isoleucine methyl ester provided an amino alcohol, which was treated with triphosgene or sodium methylate to afford a carbamate- or a morpholinone-androstane derivative, respectively. These steroid derivatives inhibited 17β-HSD3 (14–88% at 1 μM; 46–94% at 10 μM) and 17β-HSD5 (54–73% at 0.3 μM; 91–92% at 3 μM). They did not produce any androgenic activity and did not bind steroid (androgen, estrogen, glucocorticoid and progestin) receptors, suggesting a good profile for prostate cancer therapy.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.