Synthesis of N-heterocyclic carbene ligands and derived ruthenium olefin metathesis catalysts

We describe the synthesis of commonly used free N-heterocyclic carbenes (NHCs), 1,3-bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes) and 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr), and of the two corresponding ruthenium-based metathesis complexes. The complex containing IMes was found to be highly efficient in macrocyclizations involving ring-closing metatheses (RCM), whereas the complex featuring the IPr ligand shows excellent activity in both RCM and cross metathesis because of its greater stability. The free carbenes IMes and IPr are isolated in four steps, with an overall yield of ～50%. They are then used to replace a labile phosphine in precatalysts belonging to two families of ruthenium-containing complexes, benzylidene and indenylidene types, respectively. Such complexes are isolated as analytically pure compounds with 77% and 95% yield. The total time for the synthesis of the free NHCs is 56 h, and incorporation in complexes requires an additional 4-5 h.     

In vitro antimicrobial studies of new benzimidazolium salts and silver N-heterocyclic carbene complexes

A series of new benzimidazolium salts (1a–g) were synthesized from the reaction of 1-(4-vinylbenzyl)benzimidazole with various alkyl halides. These salts were used to synthesize silver N-heterocyclic carbene (Ag-NHC) complexes (2a–f). The thirteen compounds were characterized by FT-IR, NMR (¹H and ¹³C) spectroscopic methods and an elemental analysis technique. These selected candidates were tested for their in vitro antimicrobial activities. Antibacterial and antifungal results indicated that the new salts, and particularly their silver complexes, were found to be strongly effective against seven Gram (?) bacterial strains, three Gram (+) bacterial strains and one yeast (Candida albicans).     

Synthesis,characterization and antimicrobial activities of novel silver(I) complexes with coumarin substituted N-heterocyclic carbene ligands

Eight new coumarin substituted silver(I) N-heterocyclic carbene (NHC) complexes were synthesized by the interaction of the corresponding imidazolium or benzimidazolium chlorides and Ag₂O in dichloromethane at room temperature. Structures of these complexes were established on the basis of elemental analysis, ¹H NMR, ¹³C NMR, IR and mass spectroscopic techniques. The antimicrobial activities of carbene precursors and silver NHC complexes were tested against standard strains: Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and the fungi Candida albicans and Candida tropicalis. Results showed that all the compounds inhibited the growth of the all bacteria and fungi strains and some complexes performed good activities against different microorganisms. Among all the compounds, the most lipophilic complex bis[1-(4-methylene-6,8-dimethyl-2H-chromen-2-one)-3-(naphthalene-2-ylmethyl)benzimidazol-2-ylidene]silver(I) dichloro argentate (5e) was found out as the most active one.     

Discover 1: a new program to search for unusually represented DNA motifs.

DISCOVER1 (DIStribution COunter VERsion 1) is a new program that can identify DNA motifs occurring with a high deviation from the expected frequency. The program generates families of patterns, each family having a common set of defined bases. Undefined bases are inserted amongst the defined bases in different ways, thus generating the diverse patterns of each family. The occurrences of the different patterns are then compared and analysed within each family, assuming that all patterns should have the same probability of occurrence. An extensive use of computer memory, combined with the immediate sorting of counts by address calculation allow a complete counting of all DNA motifs on a single pass on the DNA sequence. This approach offers a very fast way to search for unusually distributed patterns and can identify inexact patterns as well as exact patterns.     

SYFPEITHI: database for MHC ligands and peptide motifs

 The first version of the major histocompatibility complex (MHC) databank SYFPEITHI: database for MHC ligands and peptide motifs, is now available to the general public. It contains a collection of MHC class I and class II ligands and peptide motifs of humans and other species, such as apes, cattle, chicken, and mouse, for example, and is continuously updated. All motifs currently available are accessible as individual entries. Searches for MHC alleles, MHC motifs, natural ligands, T-cell epitopes, source proteins/organisms and references are possible. Hyperlinks to the EMBL and PubMed databases are included. In addition, ligand predictions are available for a number of MHC allelic products. The database content is restricted to published data only.     

Unexpected reactivity resulting from modifications of the ligand periphery: Synthesis, structure, and spectroscopic properties of iron complexes of new tripodal N-heterocyclic carbene (NHC) ligands

The chelating ligand tris-[2-(3-aryl-imidazol-2-ylidene)ethyl]amine (TIMEN^R, R = aryl = 2,6-xylyl (xyl), mesityl (mes)) has provided access to reactive transition metal complexes. Here, two new tripodal N-heterocyclic carbene ligands of the TIMEN^R system (R = aryl = tolyl (tol), 3,5-xylyl (3,5xyl)), featuring sterically less demanding aryl substituents were synthesized. With these ligands, Fe(II) precursor complexes could be obtained, namely [(TIMEN^tol)Fe](BF₄)₂ (3) and [(TIMEN^3,5xyl)Fe(CH₃CN)](PF₆)₂ (7), which showed unexpected reactivity upon reduction. Treatment of the compounds with sodium amalgam yield the tris- and bis-metallated products, [(TIMEN^tol∗∗∗)Fe] (4) and [(TIMEN^3,5xyl∗∗)Fe] (8), respectively. While the Fe(III) complex 4 is relatively inert towards oxygen, the Fe(II) complex 8 is prone to oxidation. This oxidation of 8 can readily be observed in chlorinated solvents, producing the Fe(III) complex [(TIMEN^3,5xyl∗∗)Fe](PF₆) (9). All new ligand imidazolium precursors and metal complexes were characterized by single crystal X-ray structure determination.     

The search for new beta-cell sources

Type 1 diabetes affects an estimated 150 million people worldwide and results from an autoimmune-mediated destruction of insulin-producing beta-cells. In the United States alone more than 16 million people are affected by this disease and it is estimated that spending for diabetes management accounts for one out of every eight healthcare dollars. In this context, scientists are proposing novel therapeutic strategies that might allow a perfect glycemic control of most patients with diabetes.     

The search for new industrial crops

Advances in technological development have produced an ever-increasing pressure for new and different raw materials to keep pace with changing industrial needs. Many new and useful properties of plants may be discovered through the modern chemistry and technology of utilization research. The U. S. Department of Agriculture’s search for new industrial crops is a coordinated botanical and utilization research program.     

Ruthenium(II) carbonyl chloride complexes containing pyridine-functionalised bidentate N-heterocyclic carbenes: Synthesis, structures, and impact of the carbene ligands on catalytic activities

A series of new ruthenium(II) carbonyl chloride complexes with pyridine-functionalised N-heterocyclic carbenes [Ru(Py-NHC)(CO)₂Cl₂], [Py-NHC = 3-methyl-1-(2-pyridyl)imidazol-2-ylidene, 1 (1a and 1b); 3-methyl-1-(2-picoyl)imidazol-2-ylidene, 2 (2a and 2b); 3-methyl-1-(2-pyridyl)benzimidazolin-2-ylidene, 3 (3b); 3-methyl-1-(2-picoyl)benzimidazolin-2-ylidene, 4 (4a and 4b); 1-methyl-4-(2-pyridyl)-1,2,4-triazoline-5-ylidene, 5 (5a and 5b)] have been prepared by transmetallation from the corresponding silver carbene complexes and characterized by NMR, IR spectroscopy and elemental analysis. In these complexes with bidentate Py-NHC ligands, one CO ligand is trans to the Py ligand. In 1a, 2a, 4a, and 5a, the NHC ligand is trans to the other CO ligand, thus leaving the two Cl⁻ ligands trans to each other. In 1b, 2b, 3b, 4b, and 5b, the NHC ligands are trans to one Cl⁻ ligand, and the two Cl⁻ ligands are cis to each other. The structures for 1b, 2b, 3b and 4b have been determined by single-crystal X-ray diffraction. These complexes are efficient catalysts in the transfer hydrogenation of acetophenone and their catalytic activities are found to be influenced by electronic effect of the N-heterocyclic carbene ligands.     

Efficient search on energy minima for structure prediction of nucleic acid motifs

Structure prediction of non-canonical motifs such as mismatches, extra unmatched nucleotides or internal and hairpin loop structures in nucleic acids is of great importance for understanding the function and design of nucleic acid structures. Systematic conformational analysis of such motifs typically involves the generation of many possible combinations of backbone dihedral torsion angles for a given motif and subsequent energy minimization (EM) and evaluation. Such approach is limited due to the number of dihedral angle combinations that grows very rapidly with the size of the motif. Two conformational search approaches have been developed that allow both an effective crossing of barriers during conformational searches and the computational demand grows much less with system size then search methods that explore all combinations of backbone dihedral torsion angles. In the first search protocol single torsion angles are flipped into favorable states using constraint EM and subsequent relaxation without constraints. The approach is repeated in an iterative manner along the backbone of the structural motif until no further energy improvement is obtained. In case of two test systems, a DNA-trinucleotide loop (sequence: GCA) and a RNA tetraloop (sequence: UUCG), the approach successfully identified low energy states close to experiment for two out of five start structures. In the second method randomly selected combinations of up to six backbone torsion angles are simultaneously flipped into preset ranges by a short constraint EM followed by unconstraint EM and acceptance according to a Metropolis acceptance criterion. This combined stochastic/EM search was even more effective than the single torsion flip approach and selected low energy states for the two test cases in between two and four cases out of five start structures.     

Transmembrane helix dimerization: beyond the search for sequence motifs

Studies of the dimerization of transmembrane (TM) helices have been ongoing for many years now, and have provided clues to the fundamental principles behind membrane protein (MP) folding. Our understanding of TM helix dimerization has been dominated by the idea that sequence motifs, simple recognizable amino acid sequences that drive lateral interaction, can be used to explain and predict the lateral interactions between TM helices in membrane proteins. But as more and more unique interacting helices are characterized, it is becoming clear that the sequence motif paradigm is incomplete. Experimental evidence suggests that the search for sequence motifs, as mediators of TM helix dimerization, cannot solve the membrane protein folding problem alone. Here we review the current understanding in the field, as it has evolved from the paradigm of sequence motifs into a view in which the interactions between TM helices are much more complex. This article is part of a Special Issue entitled: Membrane protein structure and function.     

Synthesis, characterization and antimicrobial activity of new silver complexes with N-heterocyclic carbene ligands

Synthesis, structure, and antimicrobial studies of silver complexes of N-heterocyclic carbene (NHC) are reported. All the silver-NHC complexes (1a-f) were prepared from the benzimidazolium salts by the reactions with Ag₂O in dichloromethane as a solvent at room temperature. The new compounds characterized by ¹H NMR, ¹³ C NMR, IR and elemental analysis techniques which support the proposed structures. Chloro[1-(2,4,6-trimethylbenzyl)-3-(methoxyethyl)benzimidazol-2-ylidene]silver(I) complex was structurally characterized by single-crystal X-ray diffraction. A series of new Ag-NHC complexes were screened for their in vitro antimicrobial activity against a variety of Gram-positive and Gram-negative bacteria as well as for their antifungal activity against a Candida albicans and Candida tropicalis.     

A new carbene based heterobifunctional reagent. Photochemical crosslinking of aldolase

The synthesis of a new photoactivatable heterobifunctional crosslinking reagent, the N-oxysuccinimide ester of 2-carboxy-9-diazofluorene, is described. The ability of the parent chromophore 2-carbomethoxy-9-diazofluorene to insert into cyclohexane and methanol has been established. The reagent has been linked to aldolase and the stoichiometry determined. Photolysis of the probe-linked aldolase indicated that photolysis was very rapid and that the photolysed product was constituted of crosslinked dimer, trimer and tetramer. Increase in concentration of probe linked to aldolase followed by photolysis gave rise to largely tetramer and higher oligomers of aldolase. The use of this carbene-based reagent vis a vis arylazide-based reagent for studying protein crosslinking is discussed.     

Characterization of natural peptide ligands from HLA-DP2: new insights into HLA-DP peptide-binding motifs

Although natural peptide ligands of HLA-DR and HLA-DQ molecules have been extensively studied, information about peptides naturally bound to HLA-DP is limited. Here we describe HLA-DP2 peptide ligands corresponding to 24 different source proteins that were identified by peptide pool elution and mass spectrometry sequencing from HLA-DP2 molecules expressed on EBV-LCLs. Sequencing analysis led to the identification of both promiscuous and allele-specific peptides. Moreover, the alignment of the natural ligands for HLA-DP2 described here, combined with previous results from our group and others concerning HLA-DP2 antigen presentation and HLA-DP molecular modelling, provide a better understanding of HLA-DP2 peptide-binding motifs.     

Reactivities of highly unsaturated fatty acids for the hydrogenation on nickel catalyst

The reactivities of the C₂₀ highly unsaturated fatty acids (20:5, 20:4, 20:3 etc.…) during heterogeneous hydrogenation on nickel catalyst have been studied using a computer program. Three parameters are required to determine the hydrogenation rate constant of the different fatty acid classes; the C₂₀ fatty acid composition of the starting oil, the C₂₀ fatty acid composition of a partially hydrogenated oil (PHO) and the time of reaction. It is shown that, in order to minimize the experimental errors, the PHO must be selected in such a way that the induction period is over and that this oil still contains appreciable amounts of 20:5 and 20:4.Very little difference was found for the reactivities of the 20:5, 20:4 and 20:3 acids. The major difference among unsaturated fatty acids was found to be between the 20:2 and 20:1 isomers for a hydrogenation effected according to common commercial practices.The computer program is a general one also useful for the prediction of the fatty acid composition of slightly hydrogenated oils, but is not suitable for oils hydrogenated to very low iodine values, or for those containing high proportions of trans fatty acids.