title: DNA recognition: design, synthesis and biophysical characteristics of pyrrole(H) based polyamides.
abstract: N-Methyl imidazole (Im) and N-methyl pyrrole (Py)-containing polyamides that can form stacked dimers can be programmed to target specific DNA sequences in the minor groove of DNA and control gene expression. Polyamides are being investigated as potential medicinal agents for treating diseases including cancer. The naturally occurring polyamide distamycin binds as a dimer in the minor groove of DNA and recognizes sequences rich in A/T and T/A base pairs indiscriminately. Synthetic analogs of distamycin that incorporate N-methylimidazole into the heterocyclic core have been shown to bind to G/C rich sequences with a high degree of specificity. The purpose of this study is to investigate the behavior of polyamides containing the 2,5-linked N-methylpyrrole-2-carboxamide or pyrrole(H) [Py(H)] moiety upon binding to DNA. The synthesis and biophysical characteristics of two polyamides PyPyPyPy(H) 2 and ImPyPyPy(H) 3 designed to test the binding preference of a Py/Pyrrole(H) pairing [Py/Py(H)] and a [Im/Py(H)] is described. Studies utilizing circular dichroism, thermal denaturation (ΔT(M)), biosensor-surface plasmon resonance and DNase I footprinting show that an [Im/Py(H), 3] pairing prefers a G/C or C/G pairing whilst a [Py/Py(H), 2] pairing tolerates A/T or T/A base pairs and avoids a G/C base pair.
authors.affiliation: Department of Chemistry and Division of Natural and Applied Sciences, 49423, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Chavda
authors.forename: Keith
authors.initials: K
authors.lastname: Mulder
authors.forename: Toni
authors.initials: T
authors.lastname: Brown
authors.forename: Hilary
authors.initials: H
authors.lastname: Mackay
authors.forename: Balaji
authors.initials: B
authors.lastname: Babu
authors.forename: Laura
authors.initials: L
authors.lastname: Westrate
authors.forename: Amanda
authors.initials: A
authors.lastname: Ferguson
authors.forename: Shicai
authors.initials: S
authors.lastname: Lin
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kiakos
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Ramos
authors.forename: Manoj
authors.initials: M
authors.lastname: Munde
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
mesh_terms: D020856:AT Rich Sequence; D001482:Base Composition; D001665:Binding Sites; D002942:Circular Dichroism / Q000379:methods; D004247:DNA / Q000737:chemistry*; D020862:GC Rich Sequence; D007093:Imidazoles / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009757:Nylons / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D020349:Surface Plasmon Resonance / Q000379:methods
chemical_list: D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D004247:DNA