Interaction of new anthracycline antibiotics with DNA. Effects on nucleic acid synthesis and binding to DNA.
The effects of various new anthracycline antibiotics on DNA and RNA synthesis were studied using DNA polymerase I (EC 2.7.7.7), RNA polymerase (EC 2.7.7.6) obtained from Escherichia coli and reverse transcriptase obtained from avian myeloblastosis virus. Aclacinomycin A, its analogues, baumycins A1 and A2, adriamycin and daunomycin showed potent inhibitory effects on these polymerases, with calf thymus DNA as template, with IC50 values of 10-30 microM. With poly(rA) x d(pT)10 as template for reverse transcriptase, aclacinomycin A and daunomycin showed IC50 values higher than 500 microM. Baumycins B1, B2, C1, and C2 showed high IC50 values on three polymerases. Addition of excess template DNA to the reaction mixture reversed the inhibitory effect of anthracyclines. Addition of calf thymus DNA to anthracyclines caused a bathochromic and hypochromic change in the visible spectrum. Apparent binding constant for aclacinomycin A, its analogues, and adriamycin were in the range of (1-2) X 10(6) M-1. Aclacinomycin A and adriamycin also bind to heat denatured DNA, but not strongly to yeast RNA. From these results, the structure-activity relationships of new anthracyclines on DNA binding and polymerase reactions are discussed.
D000818:Animals; D000903:Antibiotics, Antineoplastic; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D008433:Mathematics; D009279:Naphthacenes / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors; D012313:RNA / Q000096:biosynthesis*; D018894:Reverse Transcriptase Inhibitors; D013053:Spectrophotometry
D000903:Antibiotics, Antineoplastic; D009279:Naphthacenes; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D012313:RNA; D004247:DNA; D012321:DNA-Directed RNA Polymerases