Solid-phase synthesis of DNA binding polyamides on oxime resin

Abstract

Control of the energetics and specificity of DNA binding polyamides is necessary for inhibition of protein–DNA complex formation and gene regulation studies. Typically, solid-phase methods using Boc monomers for synthesis have depended on Boc-β-Ala-PAM resin which affords a β-alanine-Dp tail at the C-terminus, after cleavage with N,N-dimethylaminopropylamine (Dp). To address the energetic consequences of this tail for DNA minor groove binding, we describe an alternative solid phase method employing the Kaiser oxime resin which allows the synthesis of polyamides with incrementally shortened C-terminal tails. Polyamides without Dp and having methyl amide tails rather than β-alanine show similar affinity relative to the standard β-Dp tail. The truncated tail diminishes the A,T base pair energetic preference of the β-Dp tail which will allow a greater variety of DNA sequences to be targeted by hairpin polyamides.

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