Relation between the biologic activities and chemical structures of synthetic microbial lipopeptide analogs in mice

Mitogenicity, lethal toxicity, and antitumor activity against Meth A fibrosarcoma of chemically synthesized lipopeptide analogs, S-[2,3-bis(palmitoyloxy)-2R-propyl]-N-[(2,2,2)-tri- chloroethoxycarbonyl: Troc group]-cysteinyl-seryl-seryl-asparaginyl-alanine (compound KAB-2), which contain the amino acid sequence of lipopeptide in Escherichia coli, S-[2,3-bis(palmitoyloxy)- 2R-propyl]-N-(Troc- or amino-group)-cysteinyl-asparaginyl-seryl-glycyl-glycine (compound KAB-14 or -20), which is found in the amino acid sequence of lipopeptide in Streptomyces, and the compounds binding one to six amino acids, were examined. The analogs showed the mitogenic activity toward splenocytes of C3H/He mice. Low concentrations (0.4 and 2.0 micrograms/ml) of compounds KAB-20 and -21, which have five and six amino acids, respectively, increased the incorporation of [3H]thymidine better than a high concentration (50 micrograms/ml), suggesting that KAB compounds carrying amino groups exert better mitogenicity than KAB compounds carrying Troc group. The decrease of amino acid number in lipopeptide analogs appears to result in a lowering of mitogenicity at low concentrations. KAB-14 and KAB-2 did not exhibit the lethality at a high dose of 50 micrograms/mouse in galactosamine-loaded C57BL/6 mice. By twice intravenous injections of 50 micrograms against Meth A fibrosarcoma in BALB/c mice, KAB-2 showed a higher inhibitory effect than KAB-14. Based on these results, we concluded that the difference of amino acid sequence in the synthetic lipopeptides affects the potency of biologic activities.