Predictability of designing specific binding interactions for DNA minor groove ligands from NMR spectroscopy and molecular modeling: a copper(II)-activated DNA cleaver based on Hoechst 33258.
Analogs of Hoechst 33258 have been designed and synthesized to incorporate a 3,4-catecholic or a 3,4,5-trihydroxyphenyl function in place of the 4-phenolic group of the template molecule. Molecular design was based on the three-dimensional models of the solution structures of the Hoechst 33258 and its m-hydroxy isomer which had been derived from high-field NMR spectroscopic analysis. The predicted solution structure of the catecholic analog as its minor groove complex with duplex d(CGCGAATTCGCG)2 was confirmed by direct high-resolution NMR spectroscopy combined with molecular dynamics, using NMR-derived distance restraints. While the 3,4-catecholic analog was unable to cleave DNA in the presence of Cu(II) ions, the 3,4,5-trihydroxyphenyl analog of Hoechst 33258 was found to be an effective cleaver of DNA at low concentration when activated by copper(II) ions, a difference ascribed to the inaccessibility for copper chelation of the 3,4-dihydroxy site in its minor groove complex with DNA.
Parkinson
J
J
Department of Pharmacy, University of Manchester, U.K.
Sadat-Ebrahimi
S
S
Wilton
A
A
McKie
J H
JH
Andrews
J
J
Douglas
K T
KT
D001483:Base Sequence; D006690:Bisbenzimidazole / Q000031:analogs & derivatives*; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D004587:Electrophoresis, Agar Gel; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry*
D008024:Ligands; D009838:Oligodeoxyribonucleotides; D009942:Organometallic Compounds; D003300:Copper; D004247:DNA; D006690:Bisbenzimidazole