Molecules 2013, 18(1), 914-933; doi:10.3390/molecules18010914
Article

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

Laboratory of Medicinal Chemistry, CHU de Québec (CHUL) — Research Center and Faculty of Medicine, Laval University, 2705 Laurier Boulevard, Québec (Québec), G1V 4G2, Canada These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 3 December 2012; in revised form: 24 December 2012 / Accepted: 5 January 2013 / Published: 11 January 2013
(This article belongs to the Special Issue Spiro Compounds)
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Abstract: 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.
Keywords: synthesis; steroids; spirolactone; enzyme inhibitor; 17β-hydroxysteroid dehydrogenase

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MDPI and ACS Style

Djigoué, G.B.; Ngatcha, B.T.; Roy, J.; Poirier, D. 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 2013, 18, 914-933.

AMA Style

Djigoué GB, Ngatcha BT, Roy J, Poirier D. 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. 2013; 18(1):914-933.

Chicago/Turabian Style

Djigoué, Guy B.; Ngatcha, Béatrice T.; Roy, Jenny; Poirier, Donald. 2013. "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 18, no. 1: 914-933.

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