Chemical Structure and Biochemical Activity of Cord Factor Analogs. A Comparative Study of Esters of Methyl Glcoside and Non‐Hydroxylated Fatty Acids

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Abstract
6‐Monoesters of methyl α‐D‐glucopyranoside and the even‐numbered normal chain fatty acids C14toC22 or 2‐tetradecyloctadecanoic acid (DL‐deoxy‐corynomycolic acid) have been prepared. All the normal chain fatty acid esters were devoid of toxicity for mice at the dose of 2 mg per animal, whereas the branched chain ester (deoxy‐corynomycolate) exhibited a low, bnut characteristic, toxicity.Preincubation of rat liver mitochondria with aqueous suspensions of these synthetic esters gave the following results. The shorter chain (C14 to C20) esters affected the mitochondrial respiration and coupled phosphorylation in both succinate and NADH pathways at both coupling sites II and III. The same effects were obtained by using methyl 2‐hexad3ecanoyl‐α‐D‐glucopyranoside or 6‐hexadecanoyl‐l‐asorbic acid, showing that the position of the ester linkage on the sugar residue or the conformation of the sugar moiety are not essential. Deoxycorynomyucolate induced an impairmant of mitochondrial oxidative phosphoryl;ation mainly localized at couplilng site II. Methyl 6‐do‐cosanoyl and 2,6‐sisoxoanoyl α‐D‐glucopyranosides affected only coupling site II. Inbtroductionof a double bnonmd in the fattyacid chain (docos‐13‐cis‐enote) gave results similar to those obtained with shorter chain esters.Two classes of glucoside esrters can thus be distinguished: those with a shosrtchain fattyacid part (C14 to C20), devopid of toxicitgy and affectomg pxodfatove phosphorylzation at both coupling II and III;ester of the C32‐branched chain acid exhibniting toxicity in vivo and specific inhibnition of oxidative phosphorylation at coupling site IIin vitro. Mono and diesters of docosanoic acid have an intermediate position (no toxicity, but a specific effect on mitochondria)The absence of toxicity of the short cahin ester (C14 to C22)seems to be expplained by their neutralization bty serum albumin.