Comparison of biologic activities of synthetic lipopentapeptide analogs of bacterial lipoprotein in mice.
Mitogenicity, lethal toxicity, induction of tumor necrotizing factor (TNF), and antitumor activity against Meth A fibrosarcoma of four chemically synthesized lipopentapeptide analogs, S-[2,3-bis(palmitoyloxy)-2R (designated as KAB-1), -2S(KAB-3)-propyl]-N-palmitoyl-(R)-cysteinyl-(S)-seryl- (S)-seryl-(S)-asparaginyl-(S)-alanine, S-[2,3-bis(palmitoyloxy)-2R(KAB-2), and -2S(KAB-4)-propyl]-N-[(2,2,2)-trichloroethoxycarbonyl]-(R)- cysteinyl-(S)-seryl-(S)-seryl-(S)-asparaginyl-(S)-alanine, of bacterial lipoprotein were investigated. These four analogs, as well as bacterial lipopolysaccharide (LPS) or synthetic Escherichia coli-type lipid A (506), were capable of increasing of [3H]thymidine into splenocytes of C3H/He mice. Although LPS and 506 did not exhibit the mitogenic activity in C3H/HeJ mice, KAB compounds showed remarkable mitogenicity. These analogs did not show the lethal toxicity at a high dose of 50 micrograms/mouse in galactosamine-loaded C57BL/6 mice. Peritoneal macrophages, stimulated with four analogs, caused the production of TNF which induces the L929 cell lysis in vitro. Twice, intravenous injections of 50 micrograms/mouse of these analogs showed weak growth inhibition of Meth A fibrosarcoma in BALB/c mice. The inhibitory effect of KAB-2 compound, which caused the strong TNF-induction among the four analogs, was the most potent. These results indicate that the biological activity of KAB-2 (R-configuration of the C-2 position in glycerol moiety with dipalmitoyl) is stronger than that of the other three analogs.
Shimizu
T
T
Department of Microbiology, University of Shizuoka, School of Pharmaceutical Sciences, Japan.
Ohtsuka
Y
Y
Yanagihara
Y
Y
Kurimura
M
M
Takemoto
M
M
Achiwa
K
K
D000276:Adjuvants, Immunologic; D000595:Amino Acid Sequence; D000818:Animals; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000737:chemistry / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D008074:Lipoproteins; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha