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DNA binding, solubility, and partitioning characteristics of extended lexitropsins

Record type: Article

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.

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Citation

Fishleigh, R.V., Fox, K.R., Khalaf, A.I., Pitt, A.R., Scobie, M., Suckling, C.J., Urwin, J., Waigh, R.D. and Young, S.C. (2000) DNA binding, solubility, and partitioning characteristics of extended lexitropsins Journal of Medicinal Chemistry, 43, (17), pp. 3257-3266. (doi:10.1021/jm990620e).

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Published date: 3 August 2000

Identifiers

Local EPrints ID: 56658
URI: http://eprints.soton.ac.uk/id/eprint/56658
ISSN: 0022-2623
PURE UUID: 6e5deb13-a41b-45d7-a204-ae1833696485
ORCID for K.R. Fox: ORCID iD orcid.org/0000-0002-2925-7315

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Date deposited: 21 Aug 2008
Last modified: 17 Jul 2017 14:30

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Contributors

Author: R.V. Fishleigh
Author: K.R. Fox ORCID iD
Author: A.I. Khalaf
Author: A.R. Pitt
Author: M. Scobie
Author: C.J. Suckling
Author: J. Urwin
Author: R.D. Waigh
Author: S.C. Young

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