Characterising the atypical 5'-CG DNA sequence specificity of 9-aminoacridine carboxamide Pt complexes.
In this study, the DNA sequence specificity of four DNA-targeted 9-aminoacridine carboxamide Pt complexes was compared with cisplatin, using two specially constructed plasmid templates. One plasmid contained 5'-CG and 5'-GA insert sequences while the other plasmid contained a G-rich transferrin receptor gene promoter insert sequence. The damage profiles of each compound on the different DNA templates were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. With the plasmid that contained 5'-CG and 5'-GA dinucleotides, the four 9-aminoacridine carboxamide Pt complexes produced distinctly different damage profiles as compared with cisplatin. These 9-aminoacridine complexes had greatly increased levels of DNA damage at CG and GA dinucleotides as compared with cisplatin. It was shown that the presence of a CG or GA dinucleotide was sufficient to reveal the altered DNA sequence selectivity of the 9-aminoacridine carboxamide Pt analogues. The DNA sequence specificity of the Pt complexes was also found to be similarly altered utilising the transferrin receptor DNA sequence.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
Hieronimus W
HW
Kava
Anne M
AM
Galea
Farhana
F
Md Jamil
Yue
Y
Feng
Vincent
V
Murray
D000609:Aminoacridines / Q000737:chemistry*; D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects* / Q000235:genetics*; D004249:DNA Damage; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity
D000609:Aminoacridines; D009944:Organoplatinum Compounds; C054505:9-aminoacridine-4-carboxamide; D004247:DNA; D002945:Cisplatin