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DNA Recognition: Design, Synthesis and Biophysical Characteristics of Pyrrole(H) Based Polyamides

[ Vol. 6 , Issue. 3 ]


Sameer Chavda, Keith Mulder, Toni Brown, Hilary Mackay, Balaji Babu, Laura Westrate, Amanda Ferguson, Shicai Lin, Konstantinos Kiakos, Joseph P. Ramos, Manoj Munde, W. David Wilson, John A. Hartley and Moses Lee   Pages 150 - 158 ( 9 )


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)] are described. Studies utilizing circular dichroism, thermal denaturation (..TM), 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.


Polyamides, pyrrole(H), DNA, sequence specificity, minor groove binder


Department of Chemistry and the Division of Natural and Applied Sciences, Hope College 49423, USA.

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