Interaction of cisplatin and DNA-targeted 9-aminoacridine platinum complexes with DNA.
Interaction of acridine- and 9-aminoacridinecarboxamide platinum complexes with DNA was investigated with respect to their DNA sequence specificity and kinetics of binding. The DNA sequence specificity of the compounds was quantitatively analyzed using a polymerase stop assay with the plasmid pUC19. The 9-aminoacridinecarboxamide platinum complexes exhibited a different sequence specificity to that of cisplatin, shifted away from runs of consecutive guanines (the main binding site for cisplatin). This alteration was dependent on chain length. Shorter chain length compounds (n = 2, 3) showed a greater difference in sequence specificity, while longer chain length compounds (n = 4, 5) more closely resembled cisplatin. An acridinecarboxamide platinum complex showed a similar sequence specificity to cisplatin, revealing that the major change of sequence specificity was due to the presence of the 9-amino substituent. A linear amplification system was used to investigate the time course of the reaction. The presence of an intercalating group (acridinecarboxamide or 9-aminoacridinecarboxamide) greatly increased the rate of reaction with DNA; this is proposed to be due to a different reaction mechanism with DNA (direct displacement by the N-7 of guanine).
Temple
M D
MD
School of Biochemistry and Molecular Genetics, University of New South Wales, Sydney, New South Wales 2052, Australia.
McFadyen
W D
WD
Holmes
R J
RJ
Denny
W A
WA
Murray
V
V
D000166:Acridines / Q000737:chemistry*; D001665:Binding Sites; D002945:Cisplatin / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D015394:Molecular Structure; D017671:Platinum Compounds / Q000737:chemistry*; D017422:Sequence Analysis, DNA; D013997:Time Factors
D000166:Acridines; D018736:DNA Adducts; D017671:Platinum Compounds; D004247:DNA; D002945:Cisplatin