Synthesis And Antitumor Activity of Lipid A Analogs Having A Phosphonooxyethyl Group With A- Or β-configuration At Position 1

Abstract

Three novel lipid A analogs, which have an a- or β-glycosidically bound phosphonooxyethyl group instead of the a-glycosyl phosphate group of natural lipid A, were synthesized. The first analog (2) had an a-phosphonooxyethyl group on the identical acylated disaccharide 4'-phosphate structure found in natural lipid A (from Escherichia coli) and hence differed from the latter only in the nature of the acidic group at position 1. The second one (3) had tetradecanoyl groups in place of the two (R)-3-hydroxytetradecanoyl groups bound to the 2- and 3-hydroxyl function of 2, retaining the a-phosphonooxyethyl group. The structure of the third analog (4) was the same as that of 3 except that the phosphonooxyethyl group of the former was β-oriented. Compounds 2 and 3 exhibited potent activity against Meth A at the same level as natural lipid A, whereas 4 showed less activity. This fact revealed that the glycosidic phosphate is not a prerequisite for the antitumor activity of lipopolysaccharide. It can be replaced with a phosphonooxyethyl group without any loss of activity provided that the a-anomeric configuration at C-l is retained. The replacement of the hydroxytetradecanoyl groups with tetradecanoyl groups does not change the activity either. © 1990, The Pharmaceutical Society of Japan. All rights reserved.