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Exploring delta-aromatic carboxamide foldamers and alpha-peptides compatibility
Perspectives of extension of this common project to a more ambitious proposal to be submitted to funding agencies : Short term Added value of the cooperation : The student Daniel Carbajo López has received extensive training in the design and synthesis of modified aliphatic peptides. The host group of Ivan Huc has a strong background in aromatic amide foldamer design synthesis and characterization. The project is based on the combination of the two expertises and will, if successful, lead to a wider scale collaborative project between the CombiChem unit at the PCB Barcelona and the European Institute of Chemistry and Biology in Bordeaux
Summary of the proposal :
(figures 1-4 in attached document)
Foldamers are molecules able to adopt well defined conformations stabilized by non-covalent interactions mimicking the structures of biopolymers. Interest for these compounds stems from the perspective of mimicking not only biopolymer structure but also biopolymer function. The group of Dr. Ivan Huc at IECB in Bordeaux, France is internationally recognized for its expertise in the design, synthesis and characterization of aromatic amide foldamers. Among them, octameric quinoline carboxamide (Fig. 1a) adopt highly stable helical structures stabilized by intramolecular hydrogen bonds between amide hydrogen and endocyclic quinoline nitrogen and by p-pstacking between quinoline (Q) units. This design has been validated both in solution and in the solid by NMR and crystallographic data (Fig. 1b). This helical folding leads to two interconverting enantiomeric conformers: left-handed (M) and right-handed (P) (Fig. 1c). Introduction of a chiral center at the C-terminus has been shows to bias the equilibrium in favour of one handedness in various proportion depending on the nature of the chiral group. The iso-butoxy side chain in position 4 of each quinoline ring may be replaced by other groups at an early stage of synthesis, via a Mitsunobu reaction. For example, Boc protected 3-amino-1-propanol side chains have been introduced leading, after deprotection, to a cationic hydrosoluble foldamer. Hydrophilic foldamers are highly interesting as they are an unusual class of molecules that can interact with biompolymers. One of them has been found to interact strongly with DNA Guanine rich sequences of telomers, which do not adopt a standard B DNA helix but a quadruplex structure. Circular dichroism spectra of the DNA-foldamer complex exhibit a specific band at 400 nm, showing that a preferred foldamer helix handedness is induced upon interacting with DNA.
The original folding mode of these aromatic oligoamides foldamers is strikingly different from those of a-peptides. The purpose of this project is to explore the compatibility of the quinoline folding modes and those of a-peptides, in particular dipeptidic units containing serine derived-oxazole or cystein-derived thiazole units.
Method and work plan:
The project is based on the observation that quinoline-derived d-amino acids and di-a-peptides (which also are d-amino acids) containing oxazole or thiazole possess a similar inner rim and may thus be combined in the same sequences to adopt a similar folding mode fig2. Fig. 3 shows an energy minimized model of the helical conformation of an octameric sequence suggesting a compatibility of the two folding modes.
The project will thus consist in preparing two quinoline amino acid monomers, one hydrophobic, one water soluble, and two oxazole containing dipeptide monomers, one hydrophobic (derived from leucine) and one hydrophilic (derived from lysine). These compounds will be prepared in two steps from Serine and in principle any a-amino acid, following the scheme described by Jantos & al. (Fig. 4). Sequences of 6-12 monomers will be synthesized comprised of the two hydrophobic monomers in various proportions. The same will be applied to the two water soluble monomers. Whenever possible, convergent synthetic schemes will be applied (two dimers give a tetramer, two tetramers give an octamer etc..). The folding behaviour of the oligomers will be studied in the solid state using single crystal x-ray diffraction, and in solution in either non polar or polar media using NMR and circular dichroism. The later method is particularly convenient as it allows to assess the effect of the oxazole-containing dipeptides on the overall handedness of the folded structures.