Abstract
Short oligonucleotides with cyclopalladated benzylamine moieties at their 5′-termini have been prepared to test the possibility of conferring palladacyclic anticancer agents sequence-selectivity by conjugation with a guiding oligonucleotide. Hybridization of these oligonucleotides with natural counterparts was studied by UV and CD (circular dichroism) melting experiments in the absence and presence of a competing ligand (2-mercaptoethanol). Cyclopalladated benzylamine proved to be strongly stabilizing relative to unmetalated benzylamine and modestly stabilizing relative to an extra A•T base pair. The stabilization was largely abolished in the presence of 2-mercaptoethanol, suggesting direct coordination of Pd(II) to a nucleobase of the complementary strand. In all cases, fidelity of Watson-Crick base pairing between the two strands was retained. Hybridization of the cyclopalladated oligonucleotides was characterized by relatively large negative enthalpy and entropy, consistent with stabilizing Pd(II) coordination partially offset by the entropic penalty of imposing conformational constraints on the flexible diethylene glycol linker between the oligonucleotide and the palladacyclic moiety.
Highlights
Short oligonucleotides with cyclopalladated benzylamine moieties at their 5 -termini have been prepared to test the possibility of conferring palladacyclic anticancer agents sequence-selectivity by conjugation with a guiding oligonucleotide
Hybridization of these oligonucleotides with natural counterparts was studied by UV and CD melting experiments in the absence and presence of a competing ligand (2-mercaptoethanol)
Cyclopalladated benzylamine proved to be strongly stabilizing relative to unmetalated benzylamine and modestly stabilizing relative to an extra AT base pair
Summary
The groundbreaking discovery of the antitumor activity of cisplatin [1,2] has been followed by efforts to develop more potent anticancer agents based on transition metal complexes [3–11]. Problems associated with the presently available platinum anticancer compounds, notably acquired or intrinsic resistance, limited spectrum of activity and relatively high degree of toxicity [12–14], have prompted interest in transition metals other than platinum for chemotherapeutic use [4,6–8,15]. Palladium is an attractive candidate because its coordination chemistry is similar to that of platinum [16,17]. While the relatively rapid ligand-exchange of Pd(II) should allow formation of thermodynamic (rather than kinetic) products and higher selectivity than attainable with Pt(II)-based drugs, it is likely to result in a different mode of action, at least with simple analogues [19]. No clinically approved palladium-containing drugs are presently available
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