THE INTERACTION OF DNA-TARGETED PLATINUM PHENANTHRIDINIUM COMPLEXES WITH DNA

Citation
J. Whittaker et al., THE INTERACTION OF DNA-TARGETED PLATINUM PHENANTHRIDINIUM COMPLEXES WITH DNA, Nucleic acids research, 26(17), 1998, pp. 3933-3939
Citations number
38
Categorie Soggetti
Biology
Journal title
ISSN journal
03051048
Volume
26
Issue
17
Year of publication
1998
Pages
3933 - 3939
Database
ISI
SICI code
0305-1048(1998)26:17<3933:TIODPP>2.0.ZU;2-F
Abstract
Cisplatin analogues were synthesised that consisted of platinum(ll) di amine complexes tethered via a polymethylene chain (n = 3, 5, 8 and 10 ) to a phenanthridinium cation, Both chloro and iodo leaving groups we re examined. DNA adduct formation was quantitatively analysed using a linear amplification system with the plasmid pGEM-3Zf(+). This system utilised Tag DNA polymerase to extend from an oligonucleotide primer t o 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. T he damage intensity at each site was determined by densitometry. The p latinum 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 plat ination, A reaction mechanism involving direct displacement of the chl oride by the N-7 of guanine may account for the rate increase. These r esults indicate that further development of these compounds could lead to more effective cancer chemotherapeutic agents.