1 research outputs found
Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers
The first observation of a polyamine–DNA interaction
using
2D [<sup>1</sup>H, <sup>15</sup>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 <sup>15</sup>N-labeled [{<i>trans</i>-PtClÂ(<sup>15</sup>NH<sub>3</sub>)<sub>2</sub>}<sub>2</sub>{ÎĽ-(<sup>15</sup>NH<sub>2</sub>(CH<sub>2</sub>)<sub>6</sub><sup>15</sup>NH<sub>2</sub>(CH<sub>2</sub>)<sub>6</sub><sup>15</sup>NH<sub>2</sub>)}]<sup>3+</sup> (1,1/<i>t,t</i>-6,6, <b>1</b>) and [{<i>trans</i>-PtClÂ(<sup>15</sup>NH<sub>3</sub>)<sub>2</sub>}<sub>2</sub>{ÎĽ-(<sup>15</sup>NH<sub>2</sub>(CH<sub>2</sub>)<sub>6</sub><sup>15</sup>NH<sub>2</sub>(CH<sub>2</sub>)<sub>2</sub><sup>15</sup>NH<sub>2</sub>(CH<sub>2</sub>)<sub>6</sub><sup>15</sup>NH<sub>2</sub>)}]<sup>4+</sup> (1,1/<i>t,t</i>–6,2,6, <b>1</b>′) with the self-complementary oligonucleotide 5′-{dÂ(ATATGTACATAT)<sub>2</sub>} (duplex <b>I</b>) are compared to the analogous reaction
with 1,0,1/<i>t,t,t</i> (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, <i>k</i><sub>MF</sub>, for <b>1</b> (0.87 M<sup>–1</sup> s<sup>–1</sup>) is 3.5 fold higher than for 1,0,1/<i>t,t,t</i> (0.25 M<sup>–1</sup> s<sup>–1</sup>;
the value could not be calculated for <b>1</b>′ due to
peak overlap). The evidence suggests that several conformers of the
bifunctional adduct form, whereas for 1,0,1/<i>t,t,t</i> only two discrete conformers were observed. The combined effect
of the conformers observed for <b>1</b> and <b>1</b>′
may play a crucial role in the increased potency of these novel complexes
compared to 1,0,1/<i>t,t,t</i>. Treated as a single final
product, the rate of formation of the 5′-5′ 1,4-GG IXL, <i>k</i><sub>CH</sub>, for <b>1</b> (<i>k</i><sub>CH</sub> = 4.37 × 10<sup>–5</sup> s<sup>–1</sup>) is similar to that of 1,0,1/<i>t,t,t</i>, whereas the
value for <b>1</b>′ is marginally higher (<i>k</i><sub>CH</sub> = 5.4 × 10<sup>–5</sup> s<sup>–1</sup>)