Relationship between activity and amino sugar stereochemistry of daunorubicin and adriamycin derivatives.
The effects of 4'-epi-daunorubicin, 4'-epi-adriamycin, and the corresponding beta anomers on the in vitro activity of Escherichia coli DNA polymerase I and RNA polymerase were determined and compared with the effects of the parent compounds. The observed effects parallel the cytotoxic activities, assayed by inhibition of mouse embryo fibroblast proliferation, and the inhibitory activities on DNA synthesis in cultured cells. The data indicate that the inverted configuration at position 1 of the amino sugar results in a markedly reduced biological activity. This conclusion is also substantiated by the data obtained with the beta anomer of adriamycin. A preliminary investigation on the binding properties of these derivatives suggests that the inverted configuration at C-1' produces a significant decrease in the binding to DNA. In contrast, epimerization at position 4' did not produce any significant change in activity. The relationship between biological and biochemical activity and DNA binding properties of the tested compounds are discussed with particularly reference to antitumor activity.
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D005347:Fibroblasts / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004317:Doxorubicin; D004247:DNA; D004254:DNA Nucleotidyltransferases; D012321:DNA-Directed RNA Polymerases; D003630:Daunorubicin