DNA recognition: design, synthesis and biophysical characteristics of pyrrole(H) based polyamides.
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.
Chavda
Sameer
S
Department of Chemistry and Division of Natural and Applied Sciences, 49423, USA.
Mulder
Keith
K
Brown
Toni
T
Mackay
Hilary
H
Babu
Balaji
B
Westrate
Laura
L
Ferguson
Amanda
A
Lin
Shicai
S
Kiakos
Konstantinos
K
Ramos
Joseph P
JP
Munde
Manoj
M
Wilson
W David
WD
Hartley
John A
JA
Lee
Moses
M
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
D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D004247:DNA