DNA fragment conformations in adducts with Kiteplatin

Abstract

The anticancer activity of cisplatin is triggered by its formation of intrastrand adducts involving adjacent G residues of DNA. To obtain information on the different conformers that can be formed, carrier ligands such as 2,2'-bipiperidine, which provide large steric bulk near the platinum coordination plane and decrease the dynamic motion about the Pt-N7 bonds, were introduced ("retro-modelling" approach). In the present study we investigate the effect of cis-1,4-diaminocyclohexane (cis-1,4-DACH) on the formation, stability, and stereochemistry of (cis-1,4-DACH)Pt(ss-oligo) adducts (ss-oligo = d(GpG) with 3'-and/or 5'-substituents). Interesting features of this ligand, absent in previous retro-modelling studies, include the large bite angle (expected to impede the ease of interconversion between possible conformers), the presence of two protons on each nitrogen (a characteristic associated with antitumor activity), and the absence of chiral centres. The use of cis-1,4-DACH has made it possible to detect different conformers in a system containing a primary diamine carrier ligand associated with anticancer activity and to confirm the previous hypothesis that the coexistence of different conformers established in studies of retro models having relatively bulky ligands is not an artefact resulting from carrier-ligand bulk. Moreover, the data for the (cis-1,4-DACH)Pt(d(GpG)) and (cis-1,4-DACH)Pt(d(GGTTT)) adducts indicate that at a temperature close to the physiological one (40°C) HH1 and ΔHT1 conformers are present in comparable amounts. In contrast, at low temperature (close to 0°C) the equilibrium shifts dramatically toward the more stable HH1 conformer (for the (cis-1,4-DACH)Pt(d(TGGT)) adduct the HH1 conformer is always dominant, even at high temperature). Notably, (cis-1,4-DACH)PtCl 2 (Kiteplatin) has been recently reinvestigated and found to be particularly active against colorectal cancer (including oxaliplatin-resistant phenotypes).

Computational evidence for structural consequences of kiteplatin damage on DNA

“…154 In order to examine the conformational preferences in kiteplatin-d(GpG) adduct, we turn to 170 theoretical methods. We previously reported the use of MM methods to explore the 171 conformational space of this adduct, 17 which located 54 conformations in total, with between 172 7 and 21 structures belonging to each family of conformers indicated in Scheme 1. Here, we 173 employ DFT methods to obtain more reliable predictions, and also to examine the origin of 174 observed preferences in more detail.…”

“…Of 72 particular relevance for the current work is a recent study that used 1 H and 31 P 1D and 2D 73 NMR spectroscopy to determine conformations of kiteplatin's adducts with single-stranded 74 DNA and their potential for interconversion. 17 Theoretical predictions from models based on 75 quantum mechanics (QM), molecular mechanics (MM) or a combination of these (QM/MM) 76 are increasingly used to complement such experiments. 18 A great many such studies have 77…”

“…Coordination 255 geometry is similar to that obtained for the HH1 GpG adduct, as are H8 ... H8 and hydrogen 256 bond distances: the former is sufficiently short to generate the NOE cross-peaks observed in 257 the NMR NOESY spectrum. 17 However, the flanking effect of thymidines leads to a 258 significant change in the orientation of guanines, which move closer to mutual planarity, with 259 associated changes in Pt-N7 torsion angles. For this adduct, all attempts to generate 260 alternative conformers by rotation about Pt-N bonds failed, such that we were only able to 261 locate the HH1 form, in agreement with the NMR finding of single conformation.…”

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

“…9,10 Research into kiteplatin has recently resurged, with many labs investigating the DNA binding activity of kiteplatin and synthesising platinum(IV) derivatives to improve cytotoxicity. [11][12][13][14][15][16][17]…”

A minimal structural variation can overcome tumour resistance of oxaliplatin: the case of 4,5-dehydrogenation of the cyclohexane ring

“…8 Moreover, the p-electrons will add an unprecedented nucleophilic character to the lipophilic six-carbon ring which in the platinum-DNA adduct is exposed in the major groove. 9,10 The presence of a chemically reactive carbon-carbon double bond also opens the door to additional chemical modications harbouring targeting and/or dual acting moieties.…”