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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

, ,  and *
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 synthesis; steroids; spirolactone; enzyme inhibitor; 17β-hydroxysteroid dehydrogenase
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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