Targeting multi-stranded DNA structures.
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 pi-overlap can be used to improve the affinity or specificity of the underlying DNA drug binding events.
Jenkins
T C
TC
Yorkshire Cancer Research Laboratory of Drug Design, University Cancer Medicine Unit, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK. t.c.jenkins@brad.ac.uk
D000818:Animals; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D008024:Ligands
D007364:Intercalating Agents; D008024:Ligands; D004247:DNA