Issue 1, 2009
From the journal:

Organic & Biomolecular Chemistry

Recognition and discrimination of DNA quadruplexes by acridine-peptide conjugates†

James E. Redman,a   J. M. Granadino-Roldán,b   James A. Schouten,a   Sylvain Ladame,a   Anthony P. Reszka,b   Stephen Neidleb  and  Shankar Balasubramanian*a  

* Corresponding authors

a University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, UK
E-mail: sb10031@cam.ac.uk
Fax: +44 1223 336913
Tel: +44 1223 336347

b Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK
E-mail: stephen.neidle@pharmacy.ac.uk
Fax: +44 020 7753 5970
Tel: +44 7753 5969

Abstract

We have explored a series of trisubstituted acridine-peptide conjugates for their ability to recognize and discriminate between DNA quadruplexes derived from the human telomere, and the c-kit and N-ras proto-oncogenes. Quadruplex affinity was measured as the peptide sequences were varied, together with their substitution position on the acridine, and the identity of the C-terminus (acid or amide). Surface plasmon resonance measurements revealed that all compounds bound to the human telomeric quadruplex with sub-micromolar affinity. Docking calculations from molecular modelling studies were used to model the effects of substituent orientation and peptide sequence. Modelling and experiment were in agreement that placement of the peptide over the face of the acridine is detrimental to binding affinity. The highest degrees of selectivity were observed towards the N-ras quadruplex by compounds capable of forming simultaneous contacts with their acridine and peptide moieties. The ligands that bound best displayed quadruplex affinities in the 1–5 nM range and at least 10-fold discrimination between the quadruplexes studied.

Graphical abstract: Recognition and discrimination of DNA quadruplexes by acridine-peptide conjugates

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Article information

DOI
https://doi.org/10.1039/B814682A
Article type
Paper
Submitted
22 Aug 2008
Accepted
22 Sep 2008
First published
30 Oct 2008

Org. Biomol. Chem., 2009,7, 76-84

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Recognition and discrimination of DNA quadruplexes by acridine-peptide conjugates

J. E. Redman, J. M. Granadino-Roldán, J. A. Schouten, S. Ladame, A. P. Reszka, S. Neidle and S. Balasubramanian, Org. Biomol. Chem., 2009, 7, 76 DOI: 10.1039/B814682A

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