THE FIRST SYNTHESES OF GLA-60 POSITIONAL ISOMERS AND THEIR BIOLOGICAL-ACTIVITIES

Six GLA-60 positional isomers (8, 14, 14', 20, 26, and 26') were synth esized to investigate their biological activities. Compound 8 exhibite d potent agonistic activity, while compounds 26 and 26' exhibited slig ht agonistic activity on TNF alpha production toward human monoblastic U937 cells. TNF alpha production (% control; 10 ng ml(-1) of LPS = 10 0) of compound 8 in the concentration of 10 mu M was 611, and that of lipid A in the same concentration was 651. In contrast, the difluorina ted compounds 14, 14', and 20 showed little agonistic activity on TNF alpha production. And neither compound 8 nor compounds 26 and 26' show ed antagonistic activity. On the other hand, the difluorinated compoun ds 14, 14', and 20 showed potent antagonistic activity, and inhibited the LPS-induced TNF alpha production dose-dependently. Compound 14' (1 0 mu M) inhibited in excess of 80% of the LPS-induced TNF alpha produc tion.