Biological activities of chemically synthesized 2-keto-3-deoxyoctonic acid-(alpha 2----6)-D-glucosamine analogs of lipid A

Abstract

The mitogenicity, lethal toxicity, and Shwartzman rLeaction of three derivatives of chemically synthesized 2-keto-3-deoxyoctonic acid-linked 2,3-diacyloxyacylglucosamine-4-phosphate (KDO-GlcN-4-P) were determined. The compounds, A-301 (with di-3-hexadecanoyloxytetradecanoyl at the C-2 and C-3 positions), A-303 (di-3-tetradecanoyloxytetradecanoyl), and A-305 (3-dodecanoyloxytetradecanoyl and 3-tetradecanoyloxytetradecanoyl), induced a significant incorporation of [3HJthymidine into splenocytes of C57BL/6 mice. The compounds A-301 and A-303 showed lethality at a high dose of 50 ,ug per mouse in C57BL/6 mice sensitized with D-galactosamine, whereas A-305 caused toxicity even at a dose of 10 ,ug per mouse. HIowever, the three compounds did not elicit the local Shwartzman reaction in rabbits. These findings indicate that the addition of 2-keto-3-deoxyoctonic acid enhances the mitogenic activity of 2,3-diacyloxyacylglucosamine-4-phosphate but does not affect the lethal toxicity and the induction of Shwartzman reaction.

Immunopharmacological activities of 2-keto-3-deoxyoctonic acid-(alpha 2----6)-linked 4-O-phosphono-D-glucosamine derivatives carrying N- and 3-O-acyl substituents

“…This investigation showed that binding of one KDO molecule to a hydroxy group at the C-6 position of lipid A-subunit analogs could not enhance the immunopharmacological activities, i.e., adjuvanticity, CSF-and TNF-inducing activities, and mitogenicity, of the corresponding analogs without KDO. In contrast to our results, Shimizu and colleagues reported that KDO-GLA-47 (referred to as A-303) exhibited significant mitogenic activity, while KDO-free GLA-47 (referred to as A-103) showed little or none (20,21). As we have reported previously (13,19) and confirmed in this study, the biological activities of GLA-47 are weak, although its structure is very close to that of the nonreducing sugar part of lipid A.…”