https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(00)01457-7.pdf

G-quadruplex DNA: a potential target for anti-cancer drug design

G-quadruplexes as targets for drug design.

In this article we review thermodynamic studies designed to examine the interaction of low molecular weight ligands or drugs with DNA. Over the past 10 years there has been an increase in the number of rigorous biophysical studies of DNA–drug interactions and considerable insight has been gained into the energetics of these binding reactions. The advent of high-sensitivity calorimetric techniques has meant that the energetics of DNA–drug association reactions can be probed directly and enthalpic and entropic contributions to the binding free energy established. There are two principal consequences arising from this type of work, firstly three-dimensional structures of DNA–drug complexes from X-ray and NMR studies can be put into a thermodynamic context and the energetics responsible for stabilizing the observed structures can be more fully understood. Secondly, any rational approach to structure-based drug design requires a fundamental base of knowledge where structural detail and thermodynamic data on complex formation are intimately linked. Therefore these types of studies allow a set of general guidelines to be established, which can then be used to develop drug design algorithms. In this review we describe recent breakthroughs in duplex DNA-directed drug design and also discuss how similar principles are now being used to target higher-order DNA molecules, for example, triplex (three-stranded) and tetraplex (four-stranded) structures. Copyright © 2000 John Wiley & Sons, Ltd.



Abbreviations used:
BePI	
benzo[e]pyridoindole

β	
β-alanine;

γ	
γ-aminobutyric acid;

DODC	
3,3-diethyloxadicarbocyanine;

DP	
dimethylaminopropylamide;

HP	
N-methyl-3-hydroxypyrrole;

lm	
N-methylimidazole;

Py	
N-methylpyrrole;

TFO	
triplet-forming oligonudeotide;

TRAP	
telomesase repeat amplification protocol.

Drug-DNA recognition: energetics and implications for design.

A new electrochemical biosensing strategy has been developed for trace measurements of toxic aromatic amine compounds. The device relies on the intercalative collection of aromatic amines onto the immobilized dsDNA layer followed by potentiometric stripping quantitation of the accumulated species. The enhanced sensitivity, accrued from the DNA collection process, is coupled to new selectivity dimensions provided by the structural requirements for such intercalative binding. The extent and rate of the accumulation are strongly dependent upon the structure of the aromatic amine species. Having the amino substituent in a slightly different position produces a dramatic effect upon the response. Nanomolar detection limits are obtained after a 10-min accumulation. Applicability to river water and groundwater samples is demonstrated. Such DNA-based devices hold great promise for environmental screening of toxic aromatic amines and for elucidating molecular interactions between intercalating pollutants with DNA.

DNA-Modified Electrode for the Detection of Aromatic Amines

Accumulation and trace measurements of phenothiazine drugs at DNA-modified electrodes

Molecular modeling studies [Islam, S.A., Neidle, S., Gandecha, B.M., Partridge, M., Patterson, L.H., & Brown, J.R. (1985) J. Med. Chem. 28, 857-864] have suggested that anthracene-9,10-dione (anthraquinone) derivatives substituted at the 1,4 and 1,8 positions with-NH(CH2)2NH(CH2CH3)2+ side chains intercalate with DNA with both substituents in the same groove (classical intercalation) while a similarly substituted 1,5 derivative intercalates in a threading mode with one side chain in each groove. Modeling studies also suggested that anthracene-9,10-dione (anthraquinone) derivatives substituted at the 2,6 positions with -NHCO(CH2)R (where R is a cationic group) should bind to DNA by the threading mode, and several such derivatives have been synthesized [Agbandjie, M., Jenkins, T.C., McKenna, R., Reszka, A., & Neidle, S. (1992) J. Med. Chem. 35, 1418-1429]. We have conducted stopped-flow kinetics association and dissociation experiments on the interaction of these anthraquinones with calf thymus DNA and with DNA polymers with alternating AT and GC base pairs to experimentally determine the binding mode and how the threading mode affects intercalation rates relative to similarly substituted classical intercalators. The binding modes, determined by analysis of relative rates, energies of activation, and effects of salt concentration on association and dissociation rate constants, agree completely with the modes predicted by molecular modeling methods. Association and dissociation rate constants for the threading mode are approximately a factor of 10 lower than constants for the classical intercalation mode, and the two modes, thus, have similar binding constants. Variations in rate constants for changes in cationic substituents at the 2 and 6 positions of the anthraquinone ring were surprisingly small.(ABSTRACT TRUNCATED AT 250 WORDS)

T C Jenkins

Papers

Substituent position dictates the intercalative DNA-binding mode for anthracene-9,10-dione antitumor drugs.