Targeting Multi-Stranded DNA Structures

Terence   C.   Jenkins

doi:10.2174/0929867003375551

Abstract

The design of agents targeted toward a structure-specific molecular recognition of DNA triplexes or tetraplexes (quadruplexes) is discussed, where such structures are relevant to antigene-based chemotherapies and the in situ cellular inhibition of telomerase function, respectively. Using principles that stem from the development of earlier synthetic duplex-binding ligands, together with recent findings that probe structure thermodynamic linkages and kinetic features of stability, a rational approach is developed to exploit the distinct molecular templates offered by these high-order nucleic acid biotarget systems. Such analytical techniques can usefully augment conventional drug design methods, particularly where detailed structural information is unavailable or the mode of binding to form a persistent DNA biotarget ligand complex is not established. Examples from the author ’ s laboratory are used to illustrate structure-specific (or structure-preferential) recognition and subsequent stabilization of DNA triplexes using intercalative or groove-mediated binding mechanisms, and the successful targeting of DNA tetraplexes using planar extended-aromatic ligands. In each case, chemical manipulation of the molecule by exploiting either (i) geometric isomers, (ii) redistribution of charged groups and/or H-bond donors/acceptors, or (iii) optimization of intermolecular p-overlap can be used to improve the affinity or specificity of the underlying DNA drug binding events.

Keywords: multi stranded DNA structures, agents, structure specific molecular recognition of DNA tetralexes, quadruplexs, Telomerase function, DNA biotarget ligand complex, structure preferential recognition, intercalative stabilization, groove mediated, DNA triplexes, homopurine, purine, anthracene 9 10 diones, Triplex binding ligands, berenil analogues, Groove Directed DNA triplex Binding, DNA tetraplex preferential Ligands, template directed strategie, tetraplex binders, hoogsteen H bonded planar arrangement