The antitumor effects of anthracyclines. II. The stereospecificity of the carbomethoxy group at position 10 of the class II anthracycline molecule
Duvernay, V.H.; Eubanks, D.; Perales, R.; Prestayko, A.W.; Crooke, S.T.
Molecular Pharmacology 21(1): 196-203
1982
ISSN/ISBN: 0026-895X PMID: 6957713 Document Number: 195288
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 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 [in mouse Novikoff hepatoma ascites carcinoma (NHAC) N1S1-73 cells] inhibitory potency, a 2-fold to 4-fold decrease in vitro antitumor [against mouse leukemia L-120 cells] potency, and a 4-fold to 32-fold reduction in in vivo antitumor potency. Apparently, 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. The 10-carbomethoxy group is essential for nucleolar RNA synthesis inhibition and Class II anthracycline antitumor activity. The stereochemical orientation of the carbomethoxy group at position 10 of the aglycone is also important in conferring class II anthracycline antitumor activity.