Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers

Abstract

The first observation of a polyamine-DNA interaction using 2D [(1)H, (15)N] HSQC NMR spectroscopy allows study of the role of the linker in polynuclear platinum-DNA interactions and a novel "anchoring" of the polyamine by Pt-DNA bond formation allows examination of the details of conformational B → Z transitions induced by the polyamine. The kinetics and mechanism of the stepwise formation of 5'-5' 1,4-GG interstrand cross-links (IXLs) by fully (15)N-labeled [{trans-PtCl((15)NH(3))(2)}(2){μ-((15)NH(2)(CH(2))(6)(15)NH(2)(CH(2))(6)(15)NH(2))}](3+) (1,1/t,t-6,6, 1) and [{trans-PtCl((15)NH(3))(2)}(2){μ-((15)NH(2)(CH(2))(6)(15)NH(2)(CH(2))(2)(15)NH(2)(CH(2))(6)(15)NH(2))}](4+) (1,1/t,t-6,2,6, 1') with the self-complementary oligonucleotide 5'-{d(ATATGTACATAT)(2)} (duplex I) are compared to the analogous reaction with 1,0,1/t,t,t (BBR3464) under identical conditions (pH 5.4, 298 K). Initial electrostatic interactions with the DNA are delocalized and followed by aquation to form the monoaqua monochloro species. The rate constant for monofunctional adduct formation, k(MF), for 1 (0.87 M(-1) s(-1)) is 3.5 fold higher than for 1,0,1/t,t,t (0.25 M(-1) s(-1); the value could not be calculated for 1' due to peak overlap). The evidence suggests that several conformers of the bifunctional adduct form, whereas for 1,0,1/t,t,t only two discrete conformers were observed. The combined effect of the conformers observed for 1 and 1' may play a crucial role in the increased potency of these novel complexes compared to 1,0,1/t,t,t. Treated as a single final product, the rate of formation of the 5'-5' 1,4-GG IXL, k(CH), for 1 (k(CH) = 4.37 × 10(-5) s(-1)) is similar to that of 1,0,1/t,t,t, whereas the value for 1' is marginally higher (k(CH) = 5.4 × 10(-5) s(-1)).