title: Understanding the guanidine-like cationic moiety for optimal binding into the DNA minor groove.
abstract: Based on our previous positive results with bis-guanidine-like diaromatic compounds as DNA minor groove binders, we propose a new family: bis-2-amino-1,4,5,6-tetrahydropyrimidines. According to calculated parameters, these dicationic systems would have a more suitable size and lipophilicity for binding into the minor groove than previous series. Moreover, their DFT-optimised structures and docking into an AT oligomer model show that they would bind in the minor groove with good strength and without energy penalty. Hence, we prepared compounds 4 a-c and evaluated their binding to ssDNA and poly(dA-dT)2 by thermal denaturation experiments. The results showed that 4 a (CO) and 4 d (NH) were the best DNA binders. Compared to the previous series, 4 a-d are better binders than bis-guanidiniums but poorer than bis-2-aminoimidazolinium derivatives. Moreover, circular dichroism experiments using ssDNA and poly(dA-dT)2 confirmed binding into the minor groove. Based on our computational design as well as biophysical studies, we have been able to determine that the optimal interaction of guanidine-like dications in the minor grove occurs with bis-2-aminoimidazolinium systems.
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College, University of Dublin, 152-160 Pearse St., Dublin 2 (Ireland).
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Sullivan
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
mesh_terms: D002412:Cations / Q000737:chemistry*; D019295:Computational Biology; D004247:DNA / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000187:drug effects; D015195:Drug Design; D019791:Guanidine / Q000031:analogs & derivatives* / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation / Q000187:drug effects
chemical_list: D002412:Cations; D004277:DNA, Single-Stranded; D004247:DNA; D019791:Guanidine
keywords: 2-amino-1,4,5,6-tetrahydropyrimidine; DNA thermal denaturation; circular dichroism; guanidine-like dications; minor groove binders; molecular design