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Bioorganic & medicinal chemistry

Search for the optimal linker in tandem hairpin polyamides.


PMID 12150881

Abstract

In order to target specific DNA sequences >or=10 base pairs in size by minor groove binding ligands, a search for the optimal linker in dimers of hairpin polyamides was initiated. Two series of tandem polyamides ImPyIm-(R)[ImPyIm-(R)(H2N)gamma-PyPyPy-L](HN)gamma-PyPyPy-beta-Dp (1a-e), where L represents a series of 4-8 carbon long aliphatic amino acid linkers, and ImPyIm-(R)[ImPyIm-(R)(H2N)gamma-PyPyPyIm-L](HN)gamma-PyPyPy-beta-Dp (2a-e), where L represents a series of 2-6 carbon long aliphatic amino acid linkers, were synthesized and characterized by quantitative DNase I footprinting. beta, gamma and Dp represents beta-alanine, gamma-aminobutyric acid, and 3-(dimethylamino)propylamine, respectively. It was found that the five-carbon 5-aminovaleric acid (delta), is suitable to span one base-pair (bp) of DNA when incorporated into a tandem polyamide. ImPyIm-(R)[ImPyIm-(R)(H2N)gamma-PyPyPy-delta](HN)gamma-PyPyPy-beta-Dp (1b) binds the 10 bp binding-site 5'-AGTGAAGTGA-3' with equilibrium association constant K(a)=3.2 x 10(10) M(-1) and ImPyIm-(R)[ImPyIm-(R)(H2N)gamma-PyPyPyIm-delta](HN)gamma-PyPyPy-beta-Dp (2d) binds the 11 bp binding-site 5'-AGTGATAGTGA-3' with K(a)=9.7 x 10(9) M(-1). Tandem 1b also bind the 11 bp site but with lower affinity affording a 15-fold specificity for the shorter binding site. Replacing a methylene group in the amino acid linker with an oxygen atom to form tandem polyamide ImPyIm-(R)[ImPyIm-(R)(H2N)gamma-PyPyPy-E](HN)gamma-PyPyPy-beta-Dp (4) where E represents the ether linker, resulted in that an 80-fold specificity for the 10 bp binding site over the 11 bp site.

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