Competitive formation of both long-range 5′–5′ and short-range antiparallel 3′–3′ DNA interstrand cross-links by a trinuclear platinum complex on binding to a 10-mer duplex

Abstract

2D [1H, 15N] HSQC NMR spectroscopy has been used to monitor the reaction of fully 15N-labelled [{trans-PtCl(NH3)2}2(µ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (Triplatin, BBR3464 or 1,0,1/t,t,t (15N-1)) with the self-complementary 10-mer DNA duplex 5´-{d(ACGTATACGT)2} (duplex I) at pH 5.4 and 298 K. Initial electrostatic interactions were observed in the minor groove of the duplex, followed directly by aquation to form the monoaqua monochloro species. There was evidence for two discrete monofunctional adducts, through covalent binding at the guanine N7 sites, and one had distinctly different 1H/15N chemical shifts to those observed previously in analogous reactions. Bifunctional adduct formation followed by binding at a second guanine N7 site with evidence for both the 3´-3´ 1,2-GG and 5´-5´ 1,6-GG interstrand cross-links in a ratio of 2:1. The results show that cross-link preference is kinetically controlled and will depend critically on the reaction conditions, explaining why in a previous reaction of 1 with duplex I the major adduct isolated by HPLC had two simultaneous 3´–3´ 1,2-interstrand cross-links.

A [1H,15N] Heteronuclear Single Quantum Coherence NMR Study of the Solution Reactivity of the Ruthenium‐Based Mitochondrial Calcium Uniporter Inhibitor Ru265

“…This 15 N-labeled analogue allows for the investigation of the solution behavior of Ru265 by 2-dimensional [ 1 H, 15 N] heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR) spectroscopy, a technique that has been used extensively to study the solution reactivity of precious metal anticancer agents. [13][14][15][16][17][18][19][20][21][22][23][24] In this study, we report the synthesis and characterization of this isotopically labeled compound, and employ [ 1 H, 15 N] HSQC NMR spectroscopy to study its axial chlorido ligand aquation kinetics, as well as its reactivity with several biologically relevant small molecules. Taken together, these results highlight the value of this spectroscopic technique for studying the solution reactivity of bioactive metal ammine complexes in biological environments.…”

Competitive formation of DNA linkage isomers by a trinuclear platinum complex and the influence of pre-association

“…7, 8, 14 To allow for direct comparison with previous studies (and particularly the reaction of 1,1/ t,t with duplex I ) 13 similar conditions were chosen (pH 5.4, 298 K). The 1 H NMR spectra recorded immediately after addition of 1 to duplex I showed splitting in the G7, G18 and G25 imino proton resonances (Fig.…”

“…The reaction of 15 N-1 with duplex I was followed using 1 H and 2D [ 1 H, 15 N] HSQC and 1 H NMR spectroscopy by the same NMR approach that we have used previously to study the kinetics of mechanism of interstrand crosslinking of 15 N-1 with different defined DNA duplexes. 7,8,14 To allow for direct comparison with previous studies (and particularly the reaction of 1,1/t,t with duplex I) 13 similar conditions were chosen ( pH 5.4, 298 K). The 1 H NMR spectra recorded immediately after addition of 1 to duplex I showed splitting in the G7, G18 and G25 imino proton resonances (Fig.…”

Glycans as Ligands in Bioinorganic Chemistry. Probing the Interaction of a Trinuclear Platinum Anticancer Complex with Defined Monosaccharide Fragments of Heparan Sulfate

“…The effects of preassociation on the final products of the covalent interaction are often quite subtle, and a relevant example is in the mechanism of the formation of long-range {Pt,Pt} 1,4 and 1,6-interstrand DNA–DNA cross-links formed by Triplatin ( 1 ), where minor groove preassociation affects both the kinetics and mechanism of the cross-link formation as well as the final adduct structure . Similarly, preassociation is implicated in the intimate mechanism of formation of the unique 5′–5′and antiparallel 3′–3′ directional isomers of {Pt,Pt} 1,4-interstrand cross-links. , …”