Tailoring the major groove of DNA mimic foldamers

Single-stranded, helically folded aromatic oligoamides bearing anionic phosphonate side chains have been shown to bind to some DNA-binding proteins better than DNA itself. However, these DNA mimic foldamers have until now mainly consisted of a single repeat motif, like a poly(dA:dT) DNA duplex, and contained limited sequence information. Here, we introduce new monomers designed to display different chemical functionalities in the major groove of the DNA mimics. Four new Fmoc-protected amino acid monomers have been synthesized and incorporated into oligomers. Sixteen foldamer sequences were prepared on solid phase. Their conformations in solution and in the solid state and their conformational dynamics were investigated using nuclear magnetic resonance, circular dichroism, molecular modeling, and X-ray crystallography. The results show that three of the four new monomers behaved as designed and that their introduction enhances the conformational dynamics of the DNA mimic foldamers. In a fourth case, conformational behavior proved to be more complex than expected. The modified sequences retained the ability to bind to the bacterial histone-like protein HU. These results showcase design strategies to manipulate large molecular biomimetics in which not only side chains but also main chain components are varied. The new monomers pave the way to complex DNA mimic foldamer sequences targeting proteins that recognize sequence-selective DNA-binding proteins such as transcription factors or restriction enzymes.