Chiral, sequence-definable foldamer-derived macrocycles
Toyah M. C. WarnockSundaram RajkumarMatthew P. FitzpatrickChristopher J. SerpellPaul DingwallPeter C. Knipe
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Abstract:
Nature's oligomeric macromolecules have been a long-standing source of inspiration for chemists producing foldamers. Natural systems are frequently conformationally stabilised by macrocyclisation, yet this approach has been rarely adopted in the field of foldamer chemistry. Here we present a new class of chiral cyclic trimers and tetramers formed by macrocyclisation of open-chain foldamer precursors. Symmetrical products are obtained via a [2 + 2] self-assembly approach, while full sequence control is demonstrated through linear synthesis and cyclisation of an unsymmetrical trimer. Structural characterisation is achieved through a combined X-ray and DFT approach, which indicates the tetramers adopt a near-planar conformation, while the trimers adopt a shallow bowl-like shape. Finally, a proof-of-concept experiment is conducted to demonstrate the macrocycles' capacity for cation binding.Keywords:
Foldamer
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Sequence (biology)
We used fluorescence and electronic absorption spectroscopy to study the molecular weight dependence of macromolecule-induced folding in a chain-centered meta-phenylene ethynylene (mPE) oligomer. Analogous to the ability of intrinsically unstructured proteins (IUPs) to induce folding of globular proteins in cellular environments, we show that macromolecules attached to both ends of an mPE dodecamer induce the foldamer to collapse into a presumed helical conformation. The collapse is especially prominent once the macromolecule segments become larger than ca. 50 kDa. For sufficiently large macromolecules, the conformational structuring occurs even in solvents that normally denature the foldamer. Based on these findings, chain-centered foldamers might find use as models to investigate the fundamental macromolecular physics of IUPs.
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Dodecameric protein
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Nature's oligomeric macromolecules have been a long-standing source of inspiration for chemists producing foldamers. Natural systems are frequently conformationally stabilised by macrocyclisation, yet this approach has been rarely adopted in the field of foldamer chemistry. Here we present a new class of chiral cyclic trimers and tetramers formed by macrocyclisation of open-chain foldamer precursors. Symmetrical products are obtained via a [2 + 2] self-assembly approach, while full sequence control is demonstrated through linear synthesis and cyclisation of an unsymmetrical trimer. Structural characterisation is achieved through a combined X-ray and DFT approach, which indicates the tetramers adopt a near-planar conformation, while the trimers adopt a shallow bowl-like shape. Finally, a proof-of-concept experiment is conducted to demonstrate the macrocycles' capacity for cation binding.
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Abstract 2,3,4,5‐Tetrahydropyridine trimer product: 2,3,4,5‐ Tetrahydropyridine trimer intermediate: Isotripiperidein product: β‐ (m.p. 70–73°) tripiperidein product: α‐Tripiperidein
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This note describes the design, synthesis, and conformational studies of a novel hybrid foldamer that adopts a definite compact, three-dimensional structure determined by a combined effect of the special conformational properties of the foldamer constituents. The striking feature of this de novo designed foldamer is its ability to display periodic γ-turn conformations stabilized by intramolecular hydrogen bonds. Conformational investigations by single-crystal X-ray studies, solution-state NMR, and ab initio MO theory at the HF/6-31G* level strongly support the prevalence of γ-turn motifs in both the di- and tetrapeptide foldamers, which are presumably stabilized by bifurcated hydrogen bonds in the solid and solution states. The strategy disclosed herein for the construction of hybrid foldamers with periodic γ-turn motifs has the potential to significantly augment the conformational space available for foldamer design with diverse backbone structures and conformations.
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This chapter discusses efforts along those lines and achievements in the formation of foldamer-based nanostructures in the aqueous environment. Helical foldamers are good candidates to build such artificial helix bundles. Mainly two approaches have been reported in the literature: a "top-down" approach, in which a natural peptide sequence known to form coiled coil structures is used as a starting scaffold to construct a nonnatural hybrid foldamer/peptide sequence that self-associates into bundles, or a "bottom-up" approach, in which the self-assembly is based on de novo designed amphiphilic foldamer helices with segregation of hydrophilic and lipophilic side chains. Several foldamer backbones were shown to render accessible elongated supramolecular nanostructures such as fibers, filament, and tubes akin to those formed by proteins and peptides. The chapter suggests the enticing opportunities for the creation of metal-coordinated nanostructures using appropriate oligomer sequences as foldable strands.
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