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 (normurainyldipeptide) with acridine/acridone derivatives and the synthesis of analogues of desmuramylpeptides (Chart 1, types C and D), containing acridine/ acridone derivatives have been descri bed. 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 ana logues of type C or D (Scheme 2) have an amide bond formed between the carb oxylic group of isoglutamine and the amine function of the respective acrid ine/acridone derivatives. The preliminary screening data indicate that the analogues of groups A, C, and D exhibit small cytotoxic activity, whereas s everal analogues of type B, 4b, 4c, 4e, 4g, 4h, 4i, and 4l, exhibiting pote nt in vitro cytotoxic activity against a panel of human cell lines (Table 4 ), have been selected by the National Cancer Institute (NCI) Evaluation Com mittee 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 heal thy and Ab melanoma bearing animals.