V. P. Sashi Kumar

Synthesis and structure-activity relationships of 14β-hydroxy-5α-pregnanes: pregnanes that bind to the cardiac glycoside receptor

Abstract 5α-pregnane-3β,14β,20β-triol 3-α- l -rhamnopyranoside (8) and 3β-(α- l -rhamnopyranosyloxy)-5α-pregn-14-en-20-one (14) were prepared from uzarigenin by ozonolysis followed by zinc and acetic acid reduction and glycosidation. During the glycosidation reaction leading to (8) the corresponding ortho ester (9) was also obtained. Uzarigenin α- l -rhamnopyranoside (15) also was prepared. Synthesis of 5α-pregnane-3β,14β,20β-triol (20) is described. Structures were established by analysis of their NMR spectra. The binding affinity of 5α and 5β cardenolide and pregnane derivatives as a measured in a radioligand binding assay was determined and their structure-activity relationships compared. The receptor binding affinity of the 5α derivatives is les than that of the corresponding 5β derivatives.

Synthesis of ring-A and -B substituted 17α-acetoxypregnan-20-one derivatives with potential activity on the digitalis receptor in cardiac muscle

The synthesis of C-6 substituted (methyl, hydroxy, acetoxy, methoxy, ethoxy, methoxycarbonyloxy, ethoxycarbonyloxy, fluoro, chloro, bromo) 5α,5β,C-4 unsaturated and C-4,6 unsaturated derivatives of 17α-acetoxypregn-4-ene-3,20-dione (17α-acetoxyprogesterone) are reported. A convenient synthesis of 6α-hydroxy derivatives by selective reduction of the 4-ene-3,6-dione system is described as is the formation of 6α-alkoxycarbonyl derivatives. Synthesis of a 5α-hydroxy-6-ketone via the 5β,6β-epoxide with N-bromosuccinimide is reported. A new preparation of 3α-hydroxy-5α-derivatives from the 4-en-3-one group has been carried out. 1H n.m.r. spectra are recorded. These compounds were synthesized to test for ouabain displacement activity on the digitalis receptor in cardiac muscle.

Stereoselective reduction of C-2 substituted steroid C-3 ketones with lithium tris-(R,S-1,2-dimethylpropyl)-borohydride and sodium borohydride

The effect of C-2 substitution on the stereoselective reduction of steroid C-3 ketones with lithium tris-(R,S-1,2-dimethylpropyl)-borohydride and sodium borohydride was investigated. The C-2 mono- and di-substituted chloro and methyl derivatives were predominantly reduced to one of the epimeric alcohols. The 2 alpha-chloro and 2 alpha-methyl derivatives of 17 beta-acetoxy-5 alpha-androstan-3-one undergo stereoselective reduction with lithium tris-(R,S-1,2-dimethylpropyl)-borohydride to the axial (3 alpha) alcohol as observed in the unsubstituted compound, whereas sodium borohydride gives predominantly the equatorial (3 beta) alcohol. The 2 beta-chloro, 2 beta-methyl, 2,2-dichloro, and 2,2-dimethyl derivatives are reduced predominantly to the equatorial (3 beta) alcohol by both reagents.

Structure-activity relationships of progesterone derivatives that bind to the digitalis receptor: Modifications in a and b rings

A number of progesterone derivatives, having a 17 alpha-acetoxy group and various functions at C-3 and C-6, interact at the cardiac glycoside (CG) binding site, using [3H]ouabain in a radioligand binding assay (RBA) with membranes from dog myocardium. We now report on results of structure-activity studies concerned with modification of the A and B rings as they influence potency in the RBA. Some progesterone derivatives with 5 alpha- or 5 beta-stereochemistry show weak receptor competing activity. Among the congeners highest potency is associated with the presence of C-4 or C-4,6 unsaturation and a C-6 substituent (CH3, Cl, Br) whose importance appears to reside in its steric rather than electronic character. The C-3 function may be carbonyl, 3 beta-hydroxy or 3 beta-acetoxy when associated with C-4 or C-4,6 unsaturation. In compounds with other substituents that promote activity, C-6 alpha substitution with -CH3, -Cl, or -Br strongly enhances activity; -F, -OCH3, carbonyl, or the unsubstituted compound promotes weak binding; and -OC2H5, -OAc, -OCOOCH3, or -OH eliminates binding activity. Receptor interaction with the double bond at C-4, but not C-5, appears to be particularly important for binding. The most potent analog identified thus far is chlormadinone acetate (17 alpha-acetoxy-6-chloropregna-4,6-diene-3,20-dione), which has 1/20 the potency of ouabain in the RBA. Studies to determine optimal structural requirements for CG-receptor binding by these hormonal steroid congeners, in conjunction with appropriate biological assays, may provide insight into the nature of a putative endogenous counterpart, lead to a better understanding of the mode of action of the CG and yield CG-like compounds with superior therapeutic properties.

Molecular rearrangement of 3-substituted 4-chloro-4,5-epoxide systems in ring A of steroids

Both stereoisomers of the 3-oxo-, 3-hydroxy-, and 3-acetoxy-4-chloro-4,5-epoxy derivatives of 17β-acetoxyandrostanes have been synthesized, and their thermal rearrangement products have been identified. A synthesis of the diosphenols, 17β-acetoxy-4-hydroxyandrost-4-en-3-one and 17β-acetoxy-4-hydroxyandrosta-4,6-dien-3-one, through a novel rearrangement of the 3-hydroxy- and 3-oxo-4-chloro-4,5-epoxides, respectively, is described. In addition to the chloro ketone products from the 3-acetoxy derivatives, rearrangement and elimination products were also formed. Structural determinations are based upon one- and two-dimensional 1H and 13C n.m.r. correlations and analyses.