New self-assembled supramolecular hydrogels based on dehydropeptides.

Supramolecular hydrogels rely on small molecules that self-assemble in water as a result of the cooperative effect of several relatively weak intermolecular interactions. Peptide-based low molecular weight hydrogelators have attracted enormous interest owing to the simplicity of small molecules combined with the versatility and biocompatibility of peptides. In this work, naproxen, a well known non-steroidal anti-inflammatory drug, was N-conjugated with various dehydrodipeptides to give aromatic peptide amphiphiles that resist proteolysis. Molecular dynamics simulations were used to obtain insight into the underlying molecular mechanism of self-assembly and to rationalize the design of this type of hydrogelators. The results obtained were in excellent agreement with the experimental observations. Only dehydrodipeptides having at least one aromatic amino acid gave hydrogels. The characterization of the hydrogels was carried out using transmission electron microscopy (TEM), circular dichroism (CD), fluorescence spectroscopy and also rheological assays.

Ln[DO3A-N-α-(pyrenebutanamido)propionate] complexes: optimized relaxivity and NIR optical properties.

We have proposed recently that the DO3A-N-α-(amino)propionate chelator and its amide conjugates are leads to targeted, high relaxivity, safe contrast agents for magnetic resonance imaging. In this work we illustrate further the expeditious nature and robustness of the synthetic methodologies developed by preparing the DO3A-N-(α-pyrenebutanamido)propionate chelator. Its Gd(3+) chelate retains the optimized water exchange, high stability and inertness of the parent complex. The pyrene moiety imparts concentration-dependent self-assembly properties and aggregation-sensitive fluorescence emission to the Gd(3+) complex. The Gd(3+) complex displays pyrene-centred fluorescence whilst the Yb(3+) and Nd(3+) complexes exhibit sensitized lanthanide-centred near-infrared luminescence. The aggregated form of the complex displays high relaxivity (32 mM(-1) s(-1), 20 MHz, 25 °C) thanks to simultaneous optimization of the rotational correlation time and of the water exchange rate. The relaxivity is however still limited by chelate flexibility. This report demonstrates that the DO3A-N-(α-amino)propionate chelator is a valuable platform for constructing high relaxivity CA using simple design principles and robust chemistries accessible to most chemistry labs.

Synthesis of new ß-amidodehydroaminobutyric acid derivatives and of new tyrosine derivatives using copper catalyzed C-N and C-O coupling reactions.

Several ß-amidodehydroaminobutyric acid derivatives were prepared from N,C-diprotected ß-bromodehydroaminobutyric acids and amides by a copper catalyzed C-N coupling reaction. The best reaction conditions include the use of a catalytic amount of CuI, N,N'-dimethylethylenediamine as ligand and K(2)CO(3) as base in toluene at 110 °C. The stereochemistry of the products was determined using NOE difference experiments and the results obtained are in agreement with an E-stereochemistry. Thus, the stereochemistry is maintained in the case of the E-isomers of ß-bromodehydroaminobutyric acid derivatives, but when the Z-isomers were used as substrates the reaction proceeds with inversion of configuration. The use of ß-bromodehydrodipeptides as substrates was also tested. It was found that the reaction outcome depend on the stereochemistry of the ß-bromodehydrodipeptide and on the nature of the first amino acid residue. The products isolated were the ß-amidodehydrodipeptide derivatives and/or the corresponding dihydropyrazines. The same catalytic system (CuI/N,N'-dimethylethylene diamine) was used in the C-O coupling reactions between a tyrosine derivative and aryl bromides. The new O-aryltyrosine derivatives were isolated in moderate to good yields. The photophysical properties of two of these compounds were studied in four solvents of different polarity. The results show that these compounds after deprotection can be used as fluorescence markers.

Gallium labeled NOTA-based conjugates for peptide receptor-mediated medical imaging.

We report a straightforward and efficient synthetic strategy for the synthesis of three model glycine-arginine-glycine-aspartic acid-glycine (GRGDG) conjugates based on derivatives of NOTA and of their Ga(III) complexes targeted to the integrin α(ν)ß(3) receptor. (71)Ga NMR spectroscopy showed that the Ga(III)-labeled conjugates are highly stable in aqueous solution. The (67)Ga-labeled conjugates proved to have high kinetic stability and showed a weak but specific binding to the receptors in a U87MG-glioblastoma cell line.

Synthesis of bis-amino acid derivatives by Suzuki cross-coupling, Michael addition and substitution reactions.

Several bis-amino acids were prepared using a bis-Suzuki coupling (compounds 4-8, 10), a sequential Michael addition and bis-Suzuki coupling (compounds 12, 13) and a Michael addition followed by a substitution reaction (compounds 18, 19). Thus, the pure stereoisomer of the methyl esters of N-(tert-butoxycarbonyl)-beta-bromodehydroaminobutyric acid and dehydrophenylalanine and of N-benzyloxycarbonyl-beta-bromodehydroaminobutyric acid were reacted with 1,4-phenylene-bis-boronic acid or 9,9-dioctyl-9H-fluorene-2,7-bis-boronic acid using modified Suzuki coupling conditions. The corresponding bis-dehydroamino acid derivatives were obtained in good to high yields maintaining the stereochemistry of the starting materials. This reaction was also applied successfully to a brominated dehydrodipeptide and 1,4-phenylene-bis-boronic acid showing that it could be used to create cross-links in peptide chains. An N,N-diacyldehydroalanine derivative was used in a sequential Michael addition and bis-Suzuki coupling giving a p-terphenyl bis-amino acid and a fluorenyl bis-amino acid in good yields. Two bis-alpha,beta-diamino acids were obtained by a Michael addition of 1,2,4-triazole to the methyl esters of N-(4-toluenesulfonyl), N-(tert-butoxycarbonyl) dehydroamino acids followed by treatment with ethylenediamine.