Targeting Multi-Stranded DNA Structures
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 authors 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: DNA biotarget ligand complex; DNA tetraplex preferential Ligands; DNA triplexes; Groove Directed DNA triplex Binding; Telomerase function; Triplex binding ligands; agents; anthracene 9 10 diones; berenil analogues; groove mediated; homopurine; hoogsteen H bonded planar arrangement; intercalative stabilization; multi stranded DNA structures; purine; quadruplexs; structure preferential recognition; structure specific molecular recognition of DNA te; template directed strategie; tetraplex binders
Document Type: Review Article
Publication date: January 1, 2000
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