DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3257-3266
Number of pages9
JournalJournal of Medicinal Chemistry
Volume43
Issue number17
DOIs
Publication statusPublished - 24 Aug 2000

Fingerprint

Solubility
Ligands
Hydrogen Bonding
DNA
Nylons
DNA Footprinting
Amidines
Drug Design
Membrane Lipids
Hydrophobic and Hydrophilic Interactions
Alkaloids
Base Pairing
lexitropsin
Water

Keywords

  • DNA Binding
  • polyamides
  • Extended Lexitropsins
  • ligands

Cite this

Khalaf, A. I., Pitt, A. R., Scobie, M., Suckling, C. J., Urwin, J., Waigh, R. D., ... Fox, K. R. (2000). DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins. Journal of Medicinal Chemistry, 43(17), 3257-3266. https://doi.org/10.1021/jm000118q
Khalaf, A.I. ; Pitt, A.R. ; Scobie, M. ; Suckling, C.J. ; Urwin, J. ; Waigh, R.D. ; Young, S.C. ; Fishleigh, R.V. ; Fox, K.R. / DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 17. pp. 3257-3266.
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Khalaf, AI, Pitt, AR, Scobie, M, Suckling, CJ, Urwin, J, Waigh, RD, Young, SC, Fishleigh, RV & Fox, KR 2000, 'DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins', Journal of Medicinal Chemistry, vol. 43, no. 17, pp. 3257-3266. https://doi.org/10.1021/jm000118q

DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins. / Khalaf, A.I.; Pitt, A.R.; Scobie, M.; Suckling, C.J.; Urwin, J.; Waigh, R.D.; Young, S.C.; Fishleigh, R.V.; Fox, K.R.

In: Journal of Medicinal Chemistry, Vol. 43, No. 17, 24.08.2000, p. 3257-3266.

Research output: Contribution to journalArticle

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T1 - DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins

AU - Khalaf, A.I.

AU - Pitt, A.R.

AU - Scobie, M.

AU - Suckling, C.J.

AU - Urwin, J.

AU - Waigh, R.D.

AU - Young, S.C.

AU - Fishleigh, R.V.

AU - Fox, K.R.

PY - 2000/8/24

Y1 - 2000/8/24

N2 - 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.

AB - 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.

KW - DNA Binding

KW - polyamides

KW - Extended Lexitropsins

KW - ligands

UR - http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/2000/43/i17/pdf/jm990620e.pdf

U2 - 10.1021/jm000118q

DO - 10.1021/jm000118q

M3 - Article

VL - 43

SP - 3257

EP - 3266

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -