Synthesis and antitumor activity of conjugates of muramyldipeptide, normuramyldipeptide, and desmuramylpeptides with acridine/acridone derivatives
Synthesis and antitumor activity of conjugates of muramyldipeptide, normuramyldipeptide, and desmuramylpeptides with acridine/acridone derivatives
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DOI：
10.1021/jm001115g
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发表时间：
2001-10-25
影响因子：
7.3
通讯作者：
Sosnowska, D
中科院分区：
文献类型：
--
作者：
Dzierzbicka, K;Kolodziejczyk, AM;Sosnowska, D
合成了两组(图1，A和B型)MDP和Nor-MDP(去甲基二肽)与吖啶/吖啶酮类化合物的偶联物，并合成了含有吖啶/吖啶酮类化合物的去胞壁二肽类似物(图1，C和D型)。在A型结合物中，糖部分的C6处的羟基与吖啶/吖啶酮N-取代的欧米伽-氨基烷基甲酸(方案1)酰化，而B型的结合物(表2)和三个类型C或D的类似物(方案2)具有在异谷氨酰胺的羧基和相应的吖啶/吖啶酮衍生物的胺功能之间形成的酰胺键。初步筛选数据表明，A、C和D组的类似物显示出较小的细胞毒活性，而B、4b、4c、4e、4g、4h、4i和4l类类似物在体外对一组人类细胞具有强大的细胞毒活性(表4)，已被美国国家癌症研究所(NCI)评估委员会选择进行进一步测试。类似物4b和4h在体内中空纤维试验中具有活性(表5)。类似物3a对健康和抗黑色素瘤荷瘤动物的脾NX细胞的细胞毒活性有免疫刺激作用。
The synthesis of two groups (Chart 1, types A and B) of conjugates of MDP (muramyldipeptide) and nor-MDP (normurainyldipeptide) with acridine/acridone derivatives and the synthesis of analogues of desmuramylpeptides (Chart 1, types C and D), containing acridine/ acridone derivatives have been described. In type A conjugates, the hydroxyl group at C6 of the sugar moiety was acylated with acridine/acridone N-substituted omega -aminoalkanocarboxylic acids (Scheme 1), whereas the conjugates of type B (Table 2) and three analogues of type C or D (Scheme 2) have an amide bond formed between the carboxylic group of isoglutamine and the amine function of the respective acridine/acridone derivatives. The preliminary screening data indicate that the analogues of groups A, C, and D exhibit small cytotoxic activity, whereas several analogues of type B, 4b, 4c, 4e, 4g, 4h, 4i, and 4l, exhibiting potent in vitro cytotoxic activity against a panel of human cell lines (Table 4), have been selected by the National Cancer Institute (NCI) Evaluation Committee for further testing. Analogues 4b and 4h were active in the in vivo hollow fiber assay (Table 5). Analogue 3a shows an immunostimulating effect on the cytotoxic activity of the NX cells obtained from the spleen of healthy and Ab melanoma bearing animals.