title: Biological activities and antitumor effects of synthetic lipid A analog linked N-acylated serine.
abstract: The mitogenicity, lethal toxicity, production of nitric oxide (NO), induction of tumor necrosis factor (TNF) and antitumor activity against Meth A fibrosarcoma by chemically synthesized N-acylated serine-linked non-phosphorylated (A-606 and A607) and phosphorylated (A-608) acylglucosamine-derived lipid A analog were determined. Compounds A-606, A-608 and A-103 [with (R)-3-tetradecanoyloxytetradecanoyl at the C-2 and C-3 positions] induced significant incorporation of [3H]thymidine into splenocytes of C3H/He mice at concentrations ranging from 3.13 to 50 microM. However, A-607 [with (R)-3-tetradecanoyloxytetradecanoyl and with tetradecanoyl at the C-2 and C-3 positions] showed most significant incorporation of [3H]thymidine. The compounds A-606, A-608 and A-103 did not exhibit the lethality at doses of 30 and 300 nmol/kg in C57BL/6 mice loaded with D-galactosamine, whereas A-607 caused the death of two out of six mice at a dose of 300 nmol/kg. These compounds, except A-607, exhibited little NO production by macrophages, but did cause NO production in the presence of interferon-gamma (IFN-gamma). Peritoneal macrophages, stimulated with A-606-A-608, caused production of TNF which induce L929 cell lysis in vitro, and A-608 showed high production of TNF. NO-inducible activity and induction of TNF by compound A-103 seemed to be lower than that of serine-linked derivatives. A-607, A-608 and A-103 showed antitumor activity against Meth A fibrosarcoma in BALB/c mice, and furthermore, the enhancement of antitumor activity by a combination of A-608 with muramyl dipeptide (MDP) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Microbiology, University of Shizuoka, School of Pharmaceutical Sciences, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimizu
authors.forename: K
authors.initials: K
authors.lastname: Iida
authors.forename: Y
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Yanagihara
authors.forename: K
authors.initials: K
authors.lastname: Ryoyama
authors.forename: T
authors.initials: T
authors.lastname: Asahara
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Achiwa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004354:Drug Screening Assays, Antitumor; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D012513:Sarcoma, Experimental / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide