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Open Access research with a European policy impact...

The Strathprints institutional repository is a digital archive of University of Strathclyde's Open Access research outputs. Strathprints provides access to thousands of Open Access research papers by Strathclyde researchers, including by researchers from the European Policies Research Centre (EPRC).

EPRC is a leading institute in Europe for comparative research on public policy, with a particular focus on regional development policies. Spanning 30 European countries, EPRC research programmes have a strong emphasis on applied research and knowledge exchange, including the provision of policy advice to EU institutions and national and sub-national government authorities throughout Europe.

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DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins

Khalaf, A.I. and Pitt, A.R. and Scobie, M. and Suckling, C.J. and Urwin, J. and Waigh, R.D. and Young, S.C. and Fishleigh, R.V. and Fox, K.R. (2000) DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins. Journal of Medicinal Chemistry, 43 (17). pp. 3257-3266. ISSN 0022-2623

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Abstract

Four new ligands that bind to the minor groove of DNA have been designed, synthesized, and evaluated by DNA footprinting. Two of the ligands are polyamides containing central regions with five or six N-methylpyrrole units, conferring hydrophobicity and good binding affinity but without retaining the correct spacing for hydrogen bonding in the base of the minor groove. The two remaining ligands have central regions which are head-to-head-linked polyamides, in which the linker is designed to improve the phasing of hydrogen bonding of the ligand with the floor of the minor groove. The highest affinity was obtained with the two polypyrroles without headgroup spacers, indicating that H-bond phasing is secondary in determining affinity compared to the major hydrophobic driving force. With a dimethylaminoalkyl group, representing a moiety with modest base strength, at both ends, water solubility is good and pH-partition theory predicts that penetration through lipid membranes will be enhanced, compared to strongly basic amidine analogues of the alkaloid precursors. All four compounds bind to DNA, with strong selectivity for AT sequences but some tolerance of GC base pairs and subtle individual preferences. The data show that very high affinities can be anticipated for future compounds in this series, but drug design must take account of overall physicochemical properties as well as the details of hydrogen bonding between ligands and the floor of the minor groove.