ABSTRACT
Novel fluorinated foldamers based on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-Tz-CF2) units were synthesized and their conformational behaviour was studied by NMR and molecular dynamics. Their activity on the aggregation of the human islet amyloid polypeptide (hIAPP) amyloid protein was evaluated by fluorescence spectroscopy and mass spectrometry. The fluorine labelling of these foldamers allowed the analysis of their interaction with the target protein. We demonstrated that the preferred extended conformation of homotriazolamers of 1,4-Tz-CF2 unit increases the aggregation of hIAPP, while the hairpin-like conformation of more flexible heterotriazolamers containing two 1,4-Tz-CF2 units mixed with natural amino acids from the hIAPP sequence reduces it, and more efficiently than the parent natural peptide. The longer heterotriazolamers having three 1,4-Tz-CF2 units adopting more folded hairpin-like and ladder-like structures similar to short multi-stranded ß-sheets have no effect. This work demonstrates that a good balance between the structuring and flexibility of these foldamers is necessary to allow efficient interaction with the target protein.
Subject(s)
Islet Amyloid Polypeptide , Triazoles , Islet Amyloid Polypeptide/chemistry , Islet Amyloid Polypeptide/metabolism , Humans , Triazoles/chemistry , Molecular Dynamics Simulation , Halogenation , Protein AggregatesABSTRACT
New gem-difluoroalkenes were synthesized by the dehydrofluorination of the corresponding 4-CF3-ß-lactams. An unexpected rearrangement mechanism of the ester moiety dependent on a stabilizing negative charge was observed. Hydrogenation to 4-CHF2-ß-lactams was successful from gem-difluoro-ß-lactams.
Subject(s)
Anti-Bacterial Agents , beta-Lactams , beta-Lactams/pharmacology , Anti-Bacterial Agents/pharmacology , Hydrogenation , EstersABSTRACT
The straightforward synthesis of chiral (R)- and (S)-difluoroalanine is reported. The key step is a Strecker-type reaction followed by hydrogenolysis, Fmoc protection, and acidic hydrolysis. Peptide coupling reactions at its N- and C-terminal positions provide diastereomerically pure tripeptides. On the basis of hydrophobicity index measurements, the hydrophobic contribution of difluoroalanine in a peptide chain was found to be similar to that of isoleucine for a smaller van der Waals volume of the side chain.
Subject(s)
Peptides , HydrolysisABSTRACT
This review provides a recent overview of the different synthetic routes of the N-CF3 group. This scaffold can be prepared from the desulfurization of thiocabamoyl fluorides or isothiocyanates with fluoride ions. Electrophilic and radical trifluoromethylations are also a great way to generate this motif. This report also focuses on the valorization of some N-CF3 compounds, which leads to new unknown N-trifluoromethyl derivatives. Finally, the first metabolic stability studies will be given for certain structures.
ABSTRACT
The 5-fluoro triazole amino acid scaffold prepared by halogen exchange has been incorporated into peptides. From the X-ray diffraction of the 5-fluoro triazole motif, the main observation was an important localization on one side of the negative potential surface. The fluorine atom reveals a cylindrical shape in its deformation electron density.
Subject(s)
Fluorine , Triazoles , Triazoles/chemistry , Fluorine/chemistry , Halogens/chemistry , Peptides , ElectronicsABSTRACT
We report here the synthesis of a novel family of N-CF3 hydrazines from a direct way involving the available and cheap Langlois reagent (CF3SO2Na). These derivatives have shown very high stability whatever the conditions used and are excellent precursors for building previously inaccessible N-CF3 functionalized compounds, such as substituted hydrazides, hydrazine-amino-acids, hydrazones, N-aziridines and pyrazoles.
Subject(s)
Azo Compounds/chemistry , Esters/chemistry , Hydrazines/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Indicators and Reagents/chemistry , Mesylates/chemistry , Methylation , Molecular StructureABSTRACT
The Ministère de l'Enseignement Supérieur et de la Recherche (MESR) is thanked for financial support for José Laxio Arenas. The China Scholarship Council is thanked for financial support for Yaochun Xu. The authors thank Pr. Vadim Soloshonok and TOSOH F-TECH, Inc. for the kind gift of N-terbutyl-sulfinylimine.
ABSTRACT
A mild and efficient amination of arenes with azodicarboxylates using potassium bisulfate (KHSO4) as the catalyst in 1,1,1,3,3,3-hexafluoro-2-propanol has been developed. This protocol allowed the amination of a broad range of arenes leading to corresponding hydrazides in good to excellent yields.
ABSTRACT
Mono- and disubstituted 4-CF3 ß-lactams at the C-3 position have been obtained stereoselectively under basic conditions. A wide range of function such as alcohols, alkyls, aryls, esters, and double and triple bonds have been introduced.
ABSTRACT
We report here a method of direct Friedel-Crafts benzylation of arenes with benzylic alcohols using cheap and readily available bisulfate salt as the catalyst in hexafluoroisopropanol. The catalytic system is powerful with a quite diverse group of functionalized arenes and benzylic alcohols. These mild conditions provide a straightforward synthesis of a variety of unsymmetrical diarylmethanes in high yield with good to high regioselectivity. An SN1 mechanism involving activation of the hydroxy group through a hydrogen bond is proposed.
ABSTRACT
Regioselective halogenation of arenes and heterocycles with N-halosuccinimides in fluorinated alcohols is disclosed. Under mild condition reactions, a wide diversity of halogenated arenes are obtained in good yields with high regioselectivity. Additionally, the versatility of the method is demonstrated by the development of one-pot sequential halogenation and halogenation-Suzuki cross-coupling reactions.
ABSTRACT
An effective and clean FC alkylation of indoles and electron-rich arenes with ß-nitroalkenes in HFIP was reported. The desired products are formed rapidly in excellent yields under mild conditions without the need for any additional catalysts or reagents. Further, this methodology can be applied to one-pot synthesis of biologically active tryptamine derivatives.
ABSTRACT
Pentapeptides having the sequence R-HN-Ala-Val-X-Val-Leu-OMe, where the central residue X is L-serine, L-threonine, (2S,3R)-L-CF3-threonine and (2S,3S)-L-CF3-threonine were prepared. The capacity of (2S,3S)- and (2S,3R)-CF3-threonine analogues to stabilize an extended structure when introduced in the central position of pentapeptides is demonstrated by NMR conformational studies and molecular dynamics simulations. CF3-threonine containing pentapeptides are more prone to mimic ß-strands than their natural Ser and Thr pentapeptide analogues. The proof of concept that these fluorinated ß-strand mimics are able to disrupt protein-protein interactions involving ß-sheet structures is provided. The CF3-threonine containing pentapeptides interact with the amyloid peptide Aß1-42 in order to reduce the protein-protein interactions mediating its aggregation process.
ABSTRACT
How anti-Alzheimer's drug candidates that reduce amyloid 1-42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aß1-42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aß1-42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aß1-42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic ß-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aß1-42 aggregation.
Subject(s)
Amyloid beta-Peptides/metabolism , Drug Design , Glycopeptides/pharmacology , Neuroblastoma/metabolism , Peptide Fragments/metabolism , Peptidomimetics , Protein Aggregates/drug effects , Protein Aggregation, Pathological/drug therapy , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Glycopeptides/chemical synthesis , Glycopeptides/chemistry , Humans , Molecular Structure , Neuroblastoma/pathology , Nuclear Magnetic Resonance, Biomolecular , Protein Binding/drug effects , Structure-Activity Relationship , Surface Plasmon ResonanceABSTRACT
The unique combination of hexafluoroisopropanol (HFIP) employed as solvent and hyperbaric conditions (10-15 kbar) allows unprecedented 1,4-addition of poor nucleophiles, such as aromatic amines, onto sluggish (cumbersome) Michael acceptors without any promoter or workup.
ABSTRACT
The high solubility of CO2 in hydrofluoroethers led to various cyclic carbonates with excellent selectivities and yields. The fluorinated phase increased the amount of CO2 in contact with the reagents. Reactions could be realized under mild conditions at 80 °C, under atmospheric pressure or under 5 bar.
Subject(s)
Carbon Dioxide/chemistry , Carbonates/chemistry , Ethers/chemistry , Hydrocarbons, Fluorinated/chemistryABSTRACT
The formation of an NCF3 bond or an NCF2R bond still remains scarce. An efficient direct electrophilic amination of fluoroalkyl groups was developed. Difluoroenoxysilanes reacted easily on azodicarboxylate derivatives. These results led to a novel family of NCF3 and NCF2 hydrazine derivatives.
Subject(s)
Azo Compounds/chemistry , Hydrazines/chemistry , Hydrazines/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Amination , Catalysis , Molecular StructureABSTRACT
Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid ß peptides. Aß1-42 being the most aggregative and neurotoxic amyloid peptide, we report herein the capacity of sugar-based pentapeptide analogs to modulate the Aß1-42 aggregation process using thioflavin fluorescence and transmission electron microscopy assays. The importance of the free hydroxyl groups of the sugar moiety, used as a ß-breaker element, is confirmed since hydroxylated compounds inhibit the aggregation process while benzylated ones enhance it. Furthermore, the most effective molecules were also evaluated by a recently developed capillary electrophoresis method, providing in vitro monitoring of the crucial, very early stages of the self-assembly process. This technique allowed us to investigate the effect of these compounds on the small non-fibrillar Aß1-42 oligomers suspected by several groups worldwide as highly neurotoxic. We clearly demonstrated that molecules delaying the aggregation can stabilize the monomeric peptide or promote the formation of soluble oligomeric species. In contrast, molecules that accelerate the aggregation can prevent the presence of small toxic oligomers.
Subject(s)
Amyloid beta-Peptides/chemistry , Carbohydrates/chemistry , Oligopeptides/chemistry , Peptide Fragments/chemistry , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Amyloid beta-Peptides/drug effects , Oligopeptides/drug effects , Peptide Fragments/drug effects , Protein Multimerization/drug effects , Structure-Activity RelationshipABSTRACT
Functionalized 3-trifluoromethyl-2-isoxazolines and 3-trifluoromethylisoxazoles were easily prepared from trifluoromethyl aldoxime 2 under mild conditions by using DIB as oxidant. Theoretical studies of the reactivity of trifluoroacetonitrile oxide 4 toward olefins and alkynes were carried out. The 3-trifluoromethyl-2-isoxazolines were ring-opened with NaBH4 and NiCl2 to yield the corresponding trifluoromethylated γ-amino alcohols.
ABSTRACT
We describe the synthesis of a library of new pseudopeptides and their inhibitory activity of the rabbit 20S proteasome chymotrypsin-like (ChT-L) activity. We replaced a natural α-amino acid by an α- or a ß-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 µM for molecule 24b). Structural variations influenced the inhibition of the ChT-L activity. Models of inhibitor/20S proteasome complexes corroborated the inhibition efficacies obtained by kinetic studies.