Cardenolides 359

Two syntheses have been reported for 14j8-hydroxyandrostan-17-ones which are useful intermediates in cardenolide synthesis. Photo-oxygenation of 5a-androsta-14,16-diene gave the epidioxide (296) which was transformed with base into 

14/3-hydroxy-5a-androst-15-en-17-one which was in turn hydrogenated to give 14/3-hydroxy-5a-androstan-17-one. Testosterone may be converted into 3/3-hydroxy-5/3-androstan-17-one which was transformed into 3/3,14 -dihydroxy-5 - 

Reagents i, TSNHNH2 ii, MeLi iii, m-ClC6H4C03H iv, PhSeSePh-NaBH4 v, H2O2 vi, CrOs-py vii, O2 viii, H2-Pd 

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The most difflcult pharmaceutically relevant oxidation of steroids is the introduction of a 14 -hydroxyl group. This functional group is found in heart-active steroids (cardenolides) such as digitoxigenin, which also contain a 17/J-butenolide substituent. The 14/ -hydroxyl group is easily cleaved off by dehydration and must therefore not be treated with Lewis or... 

When used at room temperature in the presence of an active platinum catalyst in an inert solvent, e.g., acetone or ethyl acetate, oxygen will oxidize nonhindered, saturated hydroxyl groups and exposed allylic alcohols. This reagent has found extensive use in sugar chemistry and is particularly suited for the selective oxidation of either 3a- or 3j -alcohols of steroids. Other hydroxyl groups on the steroid skeleton are much less sensitive to oxidation. As a result, this reaction has been used extensively in research on polyhydroxy cardiac-active principles, e.g., the cardenolides and bufadienolides, where the 3-hydroxyl group is easily oxidized without extensive oxidation or dehydration of other hydroxyl groups. The ordinarily difficult selective oxidation of the... 

A decisive solvent effect is also observed with other a,/ -epoxy ketones. Specifically, 3jS-hydroxy-16a,17a-epoxypregn-5-en-20-one and its acetate do not react with thiocyanic acid in ether or chloroform. However, the corresponding thiocyanatohydrins are formed by heating an acetic acid solution of the epoxide and potassium thiocyanate. As expected, the ring opening reaction is subject to steric hindrance. For example, 3j6-acetoxy-14f ,15f5-epoxy-5) -card-20(22)-enoIide is inert to thiocyanic acid in chloroform, whereas the 14a,15a-epoxide reacts readily under these conditions.Reactions of 14a,15a-epoxides in the cardenolide series yields isothiocyanatohydrins, e.g., (135), in addition to the normal thiocyanatohydrin, e.g., (134). 

Because of this situation, the prospect of synthesizing D-rhamnosyl cardenolides containing the unnatural, a-D-linkage was investigated. D-Rhamnose has not been reported to occur naturally, but it has been synthesized by Hudson and co-workers (4) in six steps, starting with methyl a-D-mannopyranoside. An intermediate in the synthesis is methyl... 

Assay results with the two new 1,2-cis (ft-d) cardenolides show enhanced activity as compared with the two unnatural, a-D-rhamnosides. They have potencies that fall well within the range for those of the naturally occurring cardenolides. These results support the postulate that the a-D-glycosidic linkage in cardenolides containing D-sugars is unfavorable for cardiotonic activity. 

An isomeric sugar, D-javose, is a constituent of two cardenolide glycosides (strophanthojavoside and antiarojavoside) found (42) in the seeds of Antiaris toxicaria Lesch. Degradative studies indicated (42) that javose had the structure 6-deoxy-2-0-methyl-D-allose (17) and this assignment was confirmed by two stereospecific syntheses. 

Na+/K+-ATPase. Figure 2 Specific Inhibitors of Na+/K+-ATPase. (a) Endogenous cardiac glycosides identified in mammals. Substances with a 5-membered lactone at position C17 of the steroid moiety are referred to as cardenolides, those with a 6-membered lactone as bufadienolides. (b) Palytoxin (C P NsO ) produced by corals of the genus Palythoa. 

Rostafnroxin, a Cardenolide Derivative with Antihypertensive Action... 

If 50% of Europeans with essential hypertension are affected by this disease because of an elevated secretion of endogenous ouabain, then there might be a chance to block its interaction at the cardiac glycoside binding site of Na+/K+-ATPase and thus lower blood pressure. This therapeutic approach seems to be successfiil. Recent studies provide evidence that the cardenolide analogue Rostafuroxin (PST 2238 Fig. 4) at very low concentrations can overcome the ouabain-induced tise of hypertension in experimental animals [6]. This compound has recently entered the phase I of clinical trials and is certainly a prototype of a new class of antihypertensive drugs. 

In Fig. 1 it can be seen that the reagent applied to the right-hand side of the chromatogram has, on the one hand, intensified the fluorescent zones of the cardenolides, but that there are, on the other hand, other substance zones whose fluorescence, compared with the natural fluorescence on the left-hand side of the chromatogram, has been weakened appreciably on treatment with the reagent. The reagent is not suitable for in situ quantitation. 

The cardenolides g-strophanthin (hRf 5-10), convallatoxin (hRj 30-35) and k-strophanthin (h/ j 50-55) immediately formed red-violet chromatogram zones that gradually faded. Hence, the reagent was not always suitable for quantitative work. 

The y-lactone ring of the steroid skeleton forms an intermediate cardenolide anion in alkaline medium that nucleophilically adds to the 3,5-dinitrobenzoic acid in the position ortho to the two nitro groups. A mesomerically stabilized red-violet anion is produced (Meisenheimer complex). 

P2j Z = 2 D, = 1.24 R = 0.05 for 2,421 intensities. This molecule is a cardenolide / -D-glucopyranoside. The pyranoside conformation is 4C4, with Q = 58 pm, 0 = 6°. The terminal lactone ring is planar. The conformation was compared with that of digitoxigenin by means of molecular-mechanics calculations. 

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