Marek M. Kabat

The lead structure in cardiac glycosides is 5 β,14 β-androstane-3 β,14-diol

SummaryThe purpose of the present study was to determine the lead structure in cardiac glycosides at the receptor level, i.e. the minimal structural requirement for specific and powerful receptor recognition. Accordingly 73 digitalis-like acting steroids were characterized as to the concentration effecting half-maximum inhibition of Na,K-ATPase from human cardiac muscle under standardized turnover conditions. Since the Ki value equaled the apparent KD value, K′D was expressed in terms of the apparent standard Gibbs energy change ΔGo′ of steroid interaction with Na,K-ATPase. This allowed the use of the extrathermodynamic approach as a rational way of correlating in a quantitative manner, the potency and structure of the various steroidal compounds.The results of the present analysis taken in conjunction with relevant findings reported in the literature, favour the following conclusions.1.Cassaine, canrenone, prednisolone- and progesterone-3,20-bisguanylhydrazone, and chlormadinol acetate are compounds that are not congeneric with digitalis.2.The butenolide ring of cardenolides or the analogous side-chains at C17β of 5β,14β-androstane-3β,14-diol are not pharmacophoric substructures, but merely amplifiers of the interaction energy of the steroid lead.3.All modifications of the structure, geometry and spatial relationship between the steroid nucleus and butenolide side chain of digitoxigenin all at once weaken the close fit interaction with the steroid and butenolide binding subsites of the enzyme in such way that the cardenolide derivatives interact with the receptor binding site area in whatever orientation that will minimize the Gibbs energy of the steroid-receptor-solvent system.4.The “butenolide carbonyl oxygen distance model” (Ahmed et al. 1983) for the interpretation of the differences in potency of the cardenolide derivatives describes the change in interaction energy through structural modification as a function of the entire molecule.5.5β,14β-androstane-3β,14-diol, the steroid nucleus of cardiac glycosides of the digitalis type, is the minimum structure for specific receptor recognition and the key structure for inducing protein conformational change and thus Na,K-ATPase inhibition. It is also the structural requirement for maximum contributions of the butenolide substituent at C17β and the sugar substituent at C3β-OH to the overall interaction energy, i.e. this steroid nucleus is the lead structure.6.The tridigitoxose side-chain at C3β-OH of digitalis glycosides can be more than isoenergetically replaced by glucose, 2′,3′-O-isopropylidene-rhamnose, digitoxose, rhamnose and 4′-deoxy-4′-amino-rhamnose (increasing order of interaction energy increments) indicating a remarkable degree of conformational adaptability of the sugar binding subsite.

A novel method of highly enantioselective synthesis of γ-hydroxy-β-keto phosphonates via allene oxides

Abstract Optically active γ-hydroxy-β-keto phosphonates 8 (96–97% ee) were obtained starting from 1-trimethylsilyl-1 -alkynes 1 by employing chiral allene oxides for introduction of α-hydroxy carbonyl functionality.

Enantioselective synthesis of the methylenecyclopropane derivative related to hypoglycine, from malic acid

Abstract Synthesis of (S)-methylenecyclopropaneacetic acid starting from L-(−)-malic acid, via (2S)-O-tert-butyldimethylsilyl-1,2-epoxybutan-4-ol and 1-O-tert-butyldiphenylsilyl-5-benzenesulfonyl-6-trimethylsilylhexane-1,3-diols as the key intermediates, is described.

Enantioselective synthesis of the methylenecyclopropane derivative related to hypoglycine, starting from malic acid

The methylenecyclopropane derivative 11 was synthesized from (S) malic acid via epoxide 5 and β-trimethylsilyl sulfone 6.

A novel route to 2-fluoromethyl- and 2-hydroxymethyl-4-alkyl furans via allene oxides

A four-step protocol for the synthesis of 2-fluoromethyl and 2-hydroxymethyl 4-alkyl furans 1a and 1b from a-alkyl acroleins 4 and 1-bromo-1-trimethylsilylethylene (5) via allene oxides 2 is elaborated, and is applied to the preparation of steroid furans 10, 11, 14 and 15 from α,β-unsaturated aldehyde 8.

Radical reaction of Williams’ glycinate auxiliaries with α-amidoacrylates: synthesis of orthogonally functionalized (2R,4R)- and (2R,4S)-diaminoglutamic acids

Orthogonally functionalized (2R,4S)- and (2R,4R)-diaminoglutamic acids 10, 11, and 12, 13 were obtained in three steps starting from (2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate 5, employing a radical reaction of selenide 6 with methyl 2-acetamidoacrylate 7 as a key step.

Highly enantioselective synthesis of α-fluoro ketones via allene oxides

Abstract Optically active α-fluoroketones (96–97% ee) were obtained by the regioselective opening of chiral allene oxides with anhydrous tetrabutylammonium fluoride.

The reaction of β-(trimethylsilyl)alkyl phenyl sulfones with oxiranes. A method for stereocontrolled synthesis of homoallylic alcohols

Abstract The reaction of β-trimethylsilylalkyl sulfones ( 4a – 4b ) with oxirane derivatives ( 5a – 5d , 9 ) followed by treatment of the immediate adducts with sodium hydride, affords O-trimethylsilyl homoallylic alcohols ( 7a – 7e , 11 ), mainly (Z) isomers.

Synthesis of α-fluoromethyl ketones via allene epoxides

Abstract α-Fluoromethyl ketones are formed via the reaction of allene epoxides with tetrabutylammonium fluoride trihydrate (TBAF·3H 2 O) in THF.

α-Methylene-γ-lactone fused to steroidal ring d as potential antitumor agent

Abstract Steroidal α-methylene-γ-lactone la has been synthesised from 3s-hydroxy-5-androsten-17-one 2 and showed to be active against HeLa cells.