Alkylglycidic acids: potential new hypoglycemic agents

Abstract

A series of alkylglycidic acid analogues and derivatives were synthesized and tested for their ability to inhibit long-chain fatty acid oxidation in vitro and to lower blood sugar in rats. The extent of inhibition of carnitine acyl transferase, the enzyme at the mitochondrial membrane necessary to transport long-chain fatty acids into the mitochondria for subsequent beta-oxidation, was determined for the series. Structure-activity relationships using in vitro inhibition of [1-14C]palmitic acid oxidation in rat hemidiaphragm muscle indicate that potent activity resides mainly in 2-alkyl (C12-C16) glycidates. Replacement of the oxirane ring with cyclopropyl, thiirane, or other rings diminishes activity, as does substitution of the glycidate ring at the 3-position. In vivo potency in the rat glucose tolerance test roughly parallels the hemidiaphragm results. The lead compound, methyl 2-tetradecylglycidate (8), is a potent hypoglycemic agent following oral administration to several animal species. The hypoglycemic analogues interfere with fatty acid oxidation by specific and irreversible inhibition of mitochondrial carnitine palmitoyl transferase-A.

Lipase-Catalyzed Enantioselective Synthesis of Methyl (R)- and (S)-2-Tetradecyloxiranecarboxylate through Sequential Kinetic Resolution

“…The required racemic diol 3 was obtained by osmiumcatalyzed dihydroxylation of methyl 2-methylenehexadecanoate (2), prepared from methyl malonate and 1-bromotetradecane as previously reported. 9 The reaction was carried out with tert-butyl hydroperoxide in acetone, osmium in catalytic amount, and "in situ" prepared tetraethylammonium acetate in order to avoid hydrolysis of the ester group. 10 Under these conditions, diol 3 was obtained in 73% isolated yield (Figure 1).…”

Effects of 2-(3-Methyl-cinnamyl-hydrazono)-propionate on Fatty Acid and Glucose Oxidation in the Isolated Rat Diaphragm Using 14C-Labelled Substrates. Hydrazonopropionic Acids, a New Class of Hypoglycaemic Substances, VIII

“…Like some other hypoglycaemic substances (6,8,12,13,14) 2-(3-methyl-cinnamyl-hydrazono)-propionate may increase glucose utilization in muscle by decreasing the oxidation of long-chain fatty acids according to the "glucose-fatty acid cycle" (1).…”

“…The effect of 2-(3-methyl-cinnamyl-hydrazono)-propionate on glycolysis and fatty acid oxidation in muscle has not previously been described; the purpose of the present study was to investigate this by measuring the conversion of 14 C-labelled substrates to carbon dioxide in hemidiaphragms of rats. Increased glucose consumption in muscle may make a large contribution to the hypoglycaemic effect of 2-(3-methyl-cinnamylhydrazono)-propionate.…”

β-Oxidation of α,β-Unsaturated Carbonyl Compounds

“…Through the intermediacy of an epoxide, an unsaturated ester was converted to the a,b-thioglycidate with thiourea (Scheme 127). 218 Note the reduction product that suggests the use of thiourea as yet another reagent for the preparation of aldols.…”