Structure-Activity Relationship of Chemically Synthesized Nonreducing Parts of Lipid a Analogs

Abstract

Some synthetic compounds of the nonreducing part of lipid A were found to preserve significant immunopharmacological activities of the endotoxin, at the same time showing very slight if any endotoxic activity such as pyrogenicity lethality or Shwartzman reactivity. Thus, divers activities of the endotoxin which had earlier been considered intrinsic and inseparable were shown to be separable when certain synthetic analogs of lipid A-subunit are at work. The combination of acyl components as well as phosphorylation and acylation positions in these partial structure analogs of lipid A affect the expression of biological activities of the endotoxin. Moreover, stereospecificities of acyl substituents contribute differently to enhance the various biological activities of the endotoxin. It was remarkable that protective activities of the endotoxin such as enhancing nonspecific resistance against microbial infections and antitumor activity are preserved in lipid A-subunit analogs of small molecular weight of ca. 1,000, which at the same time lose all or most toxic activity such as pyrogenicity, lethality and Shwartzman reactivity. It is hoped that new derivatives of lipid A and/or lipid A-subunit which exert only limited biological activities of endotoxin, whether they be protective or toxic, can be synthesized in order to clarify the structural requirements for expressing a given activity. Such compounds will be useful not only for promoting basic endotoxin research but also for application in clinical medicine. Further detailed experiments on the structure-activity relationships of the newly synthesized 4-O-phosphono-D-glucosamine derivatives binding acyl substituents of varying carbon chain length at the 2-N- and 3-O- positions are in progress.