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.