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.
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.
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada. donald.poirier@crchul.ulaval.ca
Guy Bertrand
GB
Djigoué
Béatrice Tchédam
BT
Ngatcha
Jenny
J
Roy
Donald
D
Poirier
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000731:Androstanes / Q000138:chemical synthesis* / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis* / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000731:Androstanes; D018931:Antineoplastic Agents, Hormonal; D002219:Carbamates; D007783:Lactones; D009025:Morpholines; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase