The antitumor effects of anthracyclines. II. The stereospecificity of the carbomethoxy group at position 10 of the class II anthracycline molecule.
The effects of marcellomycin, musettamycin, and their respective position 10 epimers mimimycin and collinemycin were compared in several systems both in vivo and in vitro. The results of these studies showed that the epimerization of the carbomethoxy-group at position 10 of the Class II anthracycline aglycone resulted in a 3-fold to 20-fold decrease in DNA-binding ability. The reduced DNA binding ability of these compounds is correlated with a 2-fold to 17-fold decrease in whole cellular nucleic acid synthesis inhibitory potency, a 2-fold to 4-fold decrease in vitro antitumor potency, and a 4-fold to 32-fold reduction in in vivo antitumor potency. These results further support the concept that a major portion of the antitumor activity of Class II anthracyclines is related to their avidity for DNA interactions and resultant disruption of normal template function. Previous studies from this laboratory have demonstrated that the 10-carbomethoxy group is essential for nucleolar RNA synthesis inhibition and Class II anthracycline antitumor activity. The current study further demonstrates that the stereochemical orientation of the carbomethoxy group at position 10 of the aglycone is also important in conferring Class II anthracycline antitumor activity.
D000818:Animals; D000903:Antibiotics, Antineoplastic; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000378:metabolism; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008968:Molecular Conformation; D009279:Naphthacenes / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D009279:Naphthacenes; D013936:Thymidine