Synthesis of Hoodigogenin A, aglycone of natural appetite suppressant glycosteroids extracted from Hoodia gordonii.

14ß-hydroxy pregnane glycosides extracted from Hoodia gordonii, a succulent plant isolated from Apocynaceae are suggested to have appetite suppressant properties in animals and humans. However, limited reports on biological studies concerning the appetite suppressant properties are available in the open literature. One reason for that is the poor availability of these glycosteroids because H. gordonii is a protected plant and the yield of extraction lies between 0.003% and 0.02%. Starting from 3α,12α-diacetoxy-pregnanone 1, we disclose in this report the synthesis of Hoodigogenin A, the aglycone of the natural 14ß-hydroxy pregnane glycosides extracted from H. Gordonii.

Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi.

This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)-3beta,20-diol. These compounds are potential inhibitors of the enzyme sterol 24-methyltransferase (24-SMT), which is a vital enzyme in the biosynthesis of ergosterol and related 24-alkyl sterols. Structure-activity studies were undertaken to understand the important features for activity against the enzyme, with the aim of increasing activity and selectivity. The compounds were evaluated for inhibition of recombinant Leishmania major 24-SMT and the effect of compounds on sterol composition and parasite proliferation. Essentially, compounds which showed good activity against the recombinant enzyme had a significant effect on the sterol composition and growth of parasites. The activity of compounds was found to be related to the basicity and stereochemical location of the nitrogen. Also, presence of an unprotected 3beta-OH seemed to be important for activity. However, some azasterols which were not good inhibitors of 24-SMT also showed antiproliferative activity, suggesting that there may be other modes of actions of these compounds.

Studies of molecular structure parameters of 20-piperidin-2-yl-5alpha-pregnan-3beta,20-diol and its N-methyl derivative: two inhibitors of Delta24(25) sterol methyl transferase and Delta24(24') sterol methyl reductase of Trypanosoma cruzi.

Molecular structural parameters of two potential drugs against Trypanosoma cruzi epimastigotes, 20-piperidin-2-yl-5alpha-pregnan-3beta,20-diol (1) and 20-N-methylpiperidin-2-yl-5alpha-pregnan-3beta, 20-diol (2) were studied using a combination of a stereoselective synthetic route, spectroscopic characterization and single-crystal X-ray analysis. Both compounds were synthesized with an R configuration at C20. This chirality is a consequence of the stereoselectivity observed during the formation of the intermediate 20-pyridin-2-yl-5alpha-pregnan-3beta,20R-diol (4). NMR data indicated that the six-membered aza ring of (2) is conformationally more restrained, in CDCl3 solution, than (1). X-ray studies showed that maximum deviations among structural molecular parameters of (1) and (2) correspond to torsion angles along the C20-C22 bonds, leading to a different relative orientation of the N atom; a critical structural parameter for the binding properties of aza-sterols to Delta(24(25)) sterol methyl transferase. Cremer-Pople parameters of the five-membered rings of (1) and (2) lie in the observed range for a family of tetracyclic fused ring systems retrieved from the CSD. The phi2 parameter of (1) lies just on the mean of the family, while phi2 of (2) deviates significantly towards the lower limit.

[Synthesis of pentadeutereted pregnanediol glucuronide]. / Sintez pentadeiterirovannogo gliukuronida pregnandiola.

The synthesis of 2,2,3,4,4-pentadeuteropregnanediol glucuronide sodium salt, an isotopically substituted analogue of the main progesterone metabolite, have been accomplished. The starting 5 beta-pregnane-3 alpha, 20 alpha-diol bis-tert-butyldimethylsilyl ether was converted by consecutive selective desilylation and oxidation into 5 beta-pregnane-20 alpha-ol-3-one 20-monoether. The latter's alpha-hydrogen atoms were exchanged for deuteriums by treatment with D2O-MeOD mixture catalysed with sodium carbonate, and 2,2,4,4-tetradeuterated 3-ketone formed was reduced by sodium borodeuteride into 2,2,3,4,4-pentadeuterated pregnanediol 20-silyl ether. The ether was glucuronidated under Koenigs-Knorr method with (2,3,4-tri-O-acetyl-alpha-D-glucopyranosylbromide) uronate in the presence of Ag2O. The completely protected pentadeuterated pregnanediol glucuronide resulted was converted into the above mentioned sodium salt by consecutive hydrofluoric acid hydrolysis and treatment with aqueous sodium bicarbonate solution.

Synthesis of specifically deuterium-labelled pregnanolone and pregnanediol sulphates for metabolic studies in humans.

A synthesis is reported of 3beta-hydroxy-5alpha-pregnan-20-one sulphate and the disulphate and 3-monosulphate of 5alpha-pregnane-3beta,20alpha-diol, labelled specifically with deuterium in high isotopic purity for metabolic studies in humans. Base-catalyzed equilibration of 3beta-hydroxy-5alpha-25R-spirostan-12-one (hemcogenin, II) with deuterium oxide, followed by removal of the 12-keto group and degradation of the sapogenin side-chain afforded 3beta-hydroxy-5alpha-[11,11-2H2]pregn-16-en-20-one (VII). Further deuterium atoms were introduced at the 3alpha and 20beta positions by reductions with sodium borodeuteride and lithium aluminum deuteride, respectively. These reactions led to 3beta-hydroxy-5alpha-[3alpha,11,11-2H3]pregnan-20-one (X; isotopic purity 87.2%) and 5alpha-[3alpha,11,11,20beta-2H4]pregnane-3beta,20alpha-diol (XIV; isotopic purity 83.9%). The 3-sulphate of the pregnanolone and the 3,20-disulphate of the pregnanediol were prepared directly form the free alcohols, while the 3-monosulphate of the pregnanediol was obtained via 5alpha-[3alpha,11,11,20beta-2H4]pregnane-3beta,20alpha-diol 20-acetate (XVII).