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Comparative Biological and Biochemical Effects of Nogalamycin and Its Analogs on L1210 Leukemia¹

Research Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

Nogalamycin, an anthracycline antibiotic, was active against L1210 leukemia in vitro and in vivo. Several new analogs synthesized recently were more active against P388 leukemia, L1210 leukemia, and/or B16 melanoma than was nogalamycin. This study compares the biological and biochemical effects of these compounds on L1210 leukemic cells. Compounds containing the nogalose moiety inhibited RNA synthesis more than DNA synthesis. Nogalamycin (50% inhibitory dose, 0.4 nmol/ml) and dis-nogamycin (50% inhibitory dose, 0.5 nmol/ml) were much more inhibitory towards RNA synthesis than was dis-nogalamycinic acid (50% inhibitory dose, 3.6 nmol/ml). These results paralleled those of cell growth inhibition as well as drug-DNA interaction as measured by circular dichroism and thermal melting of DNA, suggesting that the inhibition of RNA synthesis by these compounds was the result of a major biochemical lesion, probably mediated through the interaction with DNA. With the 7-alkyl analogs, RNA synthesis again was generally inhibited more than DNA synthesis. The dis isomers, i.e., 7-dis-O-methylnogalarol, 7-dis-O-methylnogarol, and 7-dis-O-ethylnogarol, inhibited RNA synthesis more than did the corresponding con isomers. This phenomenon correlated well with stronger interaction between the dis isomers and DNA. However, the con isomers were generally more inhibitory towards L1210 cell growth. By and large, the biochemical effects observed with the con isomers, particularly 7-con-O-methylnogarol, could not account for their biological activities which appear to be mediated through some mechanism other than their interaction with DNA. The significance of these findings is discussed in terms of drug development.

¹ This investigation was supported in part by Contract N01-CM-43753, Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health, Education, and Welfare.

² To whom requests for reprints should be addressed.

Received 4/ 4/79. Accepted 8/21/79.

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