Synthesis of 5α-androstane-17-spiro-δ-lactones with a 3-keto, 3-hydroxy, 3-spirocarbamate or 3-spiromorpholinone as inhibitors of 17ß-hydroxysteroid dehydrogenases.

We synthesized two series of androstane derivatives as inhibitors of type 3 and type 5 17ß-hydroxysteroid dehydrogenases (17ß-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 17ß-HSD3 (14-88% at 1 µM; 46-94% at 10 µM) and 17ß-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.

3Beta-alkyl-androsterones as inhibitors of type 3 17beta-hydroxysteroid dehydrogenase: inhibitory potency in intact cells, selectivity towards isoforms 1, 2, 5 and 7, binding affinity for steroid receptors, and proliferative/antiproliferative activities on AR+ and ER+ cell lines.

Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the biosynthesis of the potent androgen testosterone (T), which plays an important role in androgen-sensitive diseases. In an attempt to design compounds to lower the level of T, we designed androsterone (ADT) derivatives substituted at the position 3beta as inhibitors of type 3 17beta-HSD, and then selected the eight most potent ones (compounds 1-8) for additional studies. In an intact cell assay, they inhibited efficiently the conversion of natural substrate 4-androstene-3,17-dione into T, although they were less active in intact cells (IC50 approximately 1 microM) than in homogenated cells (IC50=57-100 nM). A study of the inhibitory potency with four other 17beta-HSDs revealed they were selective, since they do not inhibit reductive types 1, 5 and 7, nor oxidative type 2. Interestingly, they did not show any binding affinity for steroid receptors (androgen, estrogen, glucocorticoid and progestin). Only two inhibitors, 3beta-phenyl-ADT (5) and 3beta-phenylmethyl-ADT (6) showed some proliferative activities on an AR+ cell line and on an ER+ cell line, but their effects were not mediated through the androgen or estrogen receptors. This study identified selective inhibitors of type 3 17beta-HSD acting through a mixed-type inhibition, and devoid of non-suitable androgenic and estrogenic proliferative activities. The more potent inhibitors were 3beta-hexyl-ADT (2), 3beta-cyclohexylethyl-ADT (4) and 3beta-phenylethyl-ADT (7).