Mechanism of action of aclacinomycin A II. The interaction with DNA and with tubulin.
Aclacinomycin A was observed to effect the thermal denaturation of DNA and to increase Tm. The visible absorption spectrum of the antibiotic showed bathochromic and hypochromic shifts upon reaction with native and heat-denatured DNA. [14C]Aclacinomycin A was demonstrated by equilibrium dialysis to bind to DNA. Native calf thymus DNA appeared to possess one binding site per ca. 6 nucleotides for the antibiotic with an apparent association constant of ca. 1.2 x 10(6) M-1. Heat-denatured DNA showed much less affinity for the antibiotic: one binding site per ca. 6 nucleotides with an apparent binding constant of ca. 3.5 x 10(4) M-1. The difference of association constants between double- and single-stranded DNAs suggested that the antibiotic may be intercalated between base pairs of the DNA double helix. [14C]Aclacinomycin A exhibited higher affinity for poly(dAdT) than for poly(dIdC). The antibiotic showed a significant difference spectrum with porcine tubulin, indicating an interaction with tubulin. The binding to tubulin was also demontstrated by equilibrium dialysis of [14C]aclacinomycin A and tubulin.
D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism*; D003956:Dialysis; D006023:Glycoproteins / Q000378:metabolism*; D006358:Hot Temperature; D009279:Naphthacenes / Q000378:metabolism*; D009691:Nucleic Acid Denaturation; D011089:Polydeoxyribonucleotides / Q000378:metabolism; D011485:Protein Binding; D014404:Tubulin / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D006023:Glycoproteins; D009279:Naphthacenes; D011089:Polydeoxyribonucleotides; D014404:Tubulin; D004247:DNA