Synthesis and antitumor activity of conjugates of muramyldipeptide, normuramyldipeptide, and desmuramylpeptides with acridine/acridone derivatives.
The synthesis of two groups (Chart 1, types A and B) of conjugates of MDP (muramyldipeptide) and nor-MDP (normuramyldipeptide) 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 NK cells obtained from the spleen of healthy and Ab melanoma bearing animals.