Shimizu T, Iwamoto Y, Yanagihara Y, Ryoyama K, Suhara Y, Ikeda K, Achiwa K
Department of Microbiology, University of Shizuoka, School of Pharmaceutical Sciences, Japan.
Immunobiology. 1996;196(4):321-31. doi: 10.1016/S0171-2985(96)80055-6.
The mitogenicity, lethal toxicity, induction of tumor necrosis factor (TNF), production of nitric oxide (NO) and antitumor activity against Meth A fibrosarcoma by chemically synthesized N-acylated asparagine-linked (A-701, A-702 and A-703) or N-acylated serine-linked (A-607) nonphosphorylated acylglucosamine and 4-0-phosphorylated acylglucosamine (A-103) derived lipid A analogs were determined. compound A-607 (with tetradecanoyl and (R)-3-tetradecanoyloxytetradecanoyl at the C-2 and C-3 positions) induced a significant incorporation of 3H-thymidine into splenocytes of C3H/He mice at concentrations ranging from 3.13 to 50 microM, but the mitogenic activity of A-701 (2-N-acetylglucosamine), A-702 (tetradecanoyl at the C-2), and A-703 (with (R)-tetradecanoyloxytetradecanoyl and tetradecanoyl at the C-2 and C-3) was very weak. The lethality of A-703 and A-103 (with (R)-3-tetradecanoyloxytetradecanoyl at the C-2 and C-3) was weaker than that of A-607 at doses of 300 and 750 nmol/kg in C57BL/6 mice loaded with D-galactosamine. Peritoneal macrophages, stimulated with A-701-A-703, caused production of TNF which induce L929 cell lysis in vitro, and A-703 showed a high production of TNF. The compounds, except for A-607, exhibited little NO production by macrophages, but did induce the NO production in the presence of interferon gamma. Induction of TNF and NO inducible activity by A-703 was lower than that of A-607. A-703, A-607 and A-103 showed antitumor activity against Meth A fibrosarcoma in BALB/c mice. When A-703 or A-103 with muramyl dipeptide was administered, A-703 failed to show combined effects, but A-103 did. We concluded from these findings that the biological potency of asparagine compounds appears to be placed between serine- and amino-free compounds.
测定了化学合成的N-酰化天冬酰胺连接的（A-701、A-702和A-703）或N-酰化丝氨酸连接的（A-607）非磷酸化酰基葡糖胺以及4-O-磷酸化酰基葡糖胺（A-103）衍生的类脂A类似物的促有丝分裂活性、致死毒性、肿瘤坏死因子（TNF）诱导作用、一氧化氮（NO）产生以及对Meth A纤维肉瘤的抗肿瘤活性。化合物A-607（在C-2和C-3位带有十四烷酰基和（R）-3-十四烷酰氧基十四烷酰基）在浓度为3.13至50μM范围内可显著诱导3H-胸腺嘧啶掺入C3H/He小鼠的脾细胞，但A-701（2-N-乙酰葡糖胺）、A-702（在C-2位带有十四烷酰基）和A-703（在C-2和C-3位带有（R）-十四烷酰氧基十四烷酰基和十四烷酰基）的促有丝分裂活性非常弱。在给注射D-半乳糖胺的C57BL/6小鼠注射300和750 nmol/kg剂量时，A-703和A-103（在C-2和C-3位带有（R）-3-十四烷酰氧基十四烷酰基）的致死性比A-607弱。用A-701 - A-703刺激腹腔巨噬细胞可导致TNF产生，其在体外可诱导L929细胞裂解，且A-703显示出较高的TNF产生量。除A-607外，这些化合物由巨噬细胞产生的NO很少，但在存在干扰素γ的情况下可诱导NO产生。A-703诱导TNF和NO诱导活性低于A-607。A-703、A-607和A-103在BALB/c小鼠中对Meth A纤维肉瘤显示出抗肿瘤活性。当给予带有胞壁酰二肽的A-703或A-103时，A-703未显示出联合效应，但A-103显示出联合效应。我们从这些发现得出结论，天冬酰胺化合物的生物学效力似乎介于丝氨酸化合物和无氨基化合物之间。
