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.

Comparison of antitumor properties of nitracrine and amsacrine analogs.

For seven new methoxy and/or nitro derivatives of acridine antitumor drugs, nitracrine and amsacrine, biological activity in a few in vitro tests, as well as activity against experimental murine tumors Sarcoma-180 and Leukemia L1210 were investigated. Acute toxicity on mice (LD50) was also determined. High activity in vitro and specific activity against Sa-180 were found to be characteristic features of nitracrine, whereas amsacrine was characterized by high antileukemic activity. Methoxylation of position 2 of the acridine ring in both drugs suppressed their characteristic activity. Besides, substitution of the aminoalkyl side chain in nitracrine by methanesulfon-m-anisidine group suppressed its high antitumor activity, and the presence of a nitro group in position 1 of amsacrine suppressed its antileukemic activity. Comparison of biological properties of nitracrine, amsacrine and their analogs indicated differences in some steps of their mode of action.

Search for antitumor compounds. XIII. Biological studies. Antitumor properties of 20 quinolines, carbazoles, acridines nitro derivatives.

Results of the studies on antitumor activity of 20 acridines and related compounds (19 of them were new) in Sa-180-bearing mice are presented. Only several of these compounds i.e. C-258, C-829, C-874, and C-899(21) appeared to inhibit the Sa-180 growth; the activity of the two other compounds (C-783(21) and C-755(21)) requires confirmation in further experiments. The remaining 14 compounds were inactive. Some other general effects exerted by the compounds tested in Sa-180-bearing mice and some aspects of the structure-activity relationship are discussed.