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Twenty-three new derivatives of the heptaene nystatin analogue 28,29-didehydronystatin A(1) (1) (S44HP) were obtained by chemical modification of C16 carboxyl and amino groups of mycosamine. These derivatives comprised 15 carboxamides, 4 N-alkyl derivatives, 3 N-derivatives containing additional N-linked monosaccharide or disaccharide moiety (products of Amadori rearrangement), and 1 N-aminoacyl derivative. The derivatives have been tested in vitro against yeasts Candida albicans, Cryptococcus humicolus, and filamentous fungi (molds) Aspergillus niger and Fusarum oxysporum, as well as for hemolytic activity against human erythrocytes. Structure-activity relationships for the compounds obtained are discussed. The most active and least hemolytic derivative 3-(N,N-dimethylamino)propylamide of S44HP (6) was tested for acute toxicity and antifungal activity in animal model. Whereas amphotericin B and S44HP were active in vivo at doses close to the maximal tolerated dose, 6 was considerably less toxic and more active compared to these two antibiotics.

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Tris(1 alkylindol 3 yl)methanes were obtained and oxidized into tris(1 alkylindol 3 yl)methylium salts. The resulting salts are more toxic to cultured tumor cells than to non tumor ones. The cytotoxicity of tris(1 alkylindol 3 yl)methylium salts depends on the length of the substituent at the N atom of the heterocycle, increasing from an N unsubstituted derivative toward N butyl and N pentyl derivatives. A further increase in the length of the N alkyl substituent lowers the cytotoxicity. The cytotoxicity of tris(1 alkylindol 3 yl)methylium salts for tumor cells correlates with their antibacterial and antifungal activity. Tris(1 alkylindol 3 yl)methylium salts produced a cytocide effect on Gram positive microorganisms and the most active compounds, on Gram negative microorganisms as well. Similar patterns of the struc ture-activity relationship of N alkylated tris(indol 3 yl)methylium derivatives, which was ob served for various lines of tumor cells, bacteria, and fungi, suggest the general character of the mechanisms of the death of prokaryotic and eukaryotic cells induced by these compounds.

A novel way of chemical modification of the antibiotic olivomycin I at the 2¢-keto group of the side chain of the aglycone moiety was developed. Reaction of olivomycin I with the carboxymethoxylamine hemihydrochloride gave the key intermediate, 2¢-carboxymethoxime-olivomycin I, which was further reacted with different amines in the presence of benzotriazol-1-yl-oxytrispyrrolidinophosphonium hexafluorophosphate to give the corresponding amides. The antiproliferative and topoisomerase I (Topo-I)-poisoning activities of the novel derivatives were examined. One of the novel derivatives showed a marked inhibitory activity against Topo-I, a pronounced antitumor activity in in vivo experiments on mice bearing leukemia P-388 and lower toxic side effects compared with the parent olivomycin I.

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The inducers of microsomal drug-metabolizing enzymes phenobarbital (PB) and 20-methylcholanthrene (MC) inhibited the lethargic effect of high doses of ftorafur in C57BL/6j mice, but stimulated the animal mortality at days 4-8 after the drug administration. The opposite effect has been obtained by the combination of ftorafur with the inhibitor of the microsomal enzymes SKF 525A. Animal pretreatment with PB or with PB + MC markedly enhanced the antineoplastic activity of ftorafur in Rauscher leukemia-, leukemia La-, or hemangiopericytoma-bearing mice but seemed unlikely to afford any therapeutic advantage over this drug because the lethal toxicity of ftorafur was increased.

The paper presents the results of the study of «acute» toxicity and some results of the study of «subchronic» toxicity of Ormustin, a new anticancer drug belonging to nitrosourea class, in small laboratory animals. In the experiments the laboratory animals - hybrid mice (C57Bl/6J×DBA/2)F1 male and female and outbred male and female rats have been used. On the results of study has been obtained the calculated toxic doses of Ormustin at intravenous administration of the drug in mice and rats; has been given the preliminary assessment of the impact of Ormustin on organs and systems of rats at multiple intravenous administration.