The interaction of DNA-targeted platinum phenanthridinium complexes with DNA.
Cisplatin analogues were synthesised that consisted of platinum(II) diamine complexes tethered via a polymethylene chain ( n = 3, 5, 8 and 10) to a phenanthridinium cation. Both chloro and iodo leaving groups were examined. DNA adduct formation was quantitatively analysed using a linear amplification system with the plasmid pGEM-3Zf(+). This system utilised Taq DNA polymerase to extend from an oligonucleotide primer to the damage site. This damage site inhibited the extension of the DNA polymerase. The products were electrophoresed on a DNA sequencing gel enabling adduct formation to be determined at base pair resolution. The damage intensity at each site was determined by densitometry. The platinum phenanthridinium complexes were shown to damage DNA at shorter incubation times than cisplatin. To produce similar levels of damage, an 18 h incubation was required for cisplatin compared to 30 min for the n = 3 platinum phenanthridinium complexes; this indicates that the intercalating chromophore causes a large increase in the rate of platination. A reaction mechanism involving direct displacement of the chloride by the N-7 of guanine may account for the rate increase. These results indicate that further development of these compounds could lead to more effective cancer chemotherapeutic agents.
School of Biochemistry and Molecular Genetics and School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
J
J
Whittaker
W D
WD
McFadyen
G
G
Wickham
L P
LP
Wakelin
V
V
Murray
D000970:Antineoplastic Agents / Q000378:metabolism*; D001483:Base Sequence; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000378:metabolism*; D018736:DNA Adducts; D004249:DNA Damage; D008956:Models, Chemical; D010617:Phenanthridines
D000970:Antineoplastic Agents; D018736:DNA Adducts; D010617:Phenanthridines; C014740:phenanthridinium; D002945:Cisplatin