Multicomponent Reactions Accelerated by Aqueous Micelles

Multicomponent reactions are powerful synthetic tools for the efficient creation of complex organic molecules in an one-pot one-step fashion. Moreover, the amount of solvents and energy needed for separation and purification of intermediates is significantly reduced what is beneficial from the green chemistry issues point of view. This review highlights the development of multicomponent reactions conducted using aqueous micelles systems during the last two decades

Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma

Burkitt lymphoma is a fast-growing tumor derived from germinal center B cells. It is mainly treated with aggressive chemotherapy, therefore novel therapeutic approaches are needed due to treatment toxicity and developing resistance. Disturbance of red-ox homeostasis has recently emerged as an efficient antitumor strategy. Peroxiredoxins (PRDXs) are thioredoxin-family antioxidant enzymes that scavenge cellular peroxides and contribute to red-ox homeostasis. PRDXs are robustly expressed in various malignancies and critically involved in cell proliferation, differentiation and apoptosis. To elucidate potential role of PRDXs in lymphoma, we studied their expression level in B cell-derived primary lymphoma cells as well as in cell lines. We found that PRDX1 and PRDX2 are upregulated in tumor B cells as compared with normal counterparts. Concomitant knockdown of PRDX1 and PRDX2 significantly attenuated the growth rate of lymphoma cells. Furthermore, in human Burkitt lymphoma cell lines, we isolated dimeric 2-cysteine peroxiredoxins as targets for SK053, a novel thiol-specific small-molecule peptidomimetic with antitumor activity. We observed that treatment of lymphoma cells with SK053 triggers formation of covalent PRDX dimers, accumulation of intracellular reactive oxygen species, phosphorylation of ERK1/2 and AKT and leads to cell cycle arrest and apoptosis. Based on site-directed mutagenesis and modeling studies, we propose a mechanism of SK053-mediated PRDX crosslinking, involving double thioalkylation of active site cysteine residues. Altogether, our results suggest that peroxiredoxins are novel therapeutic targets in Burkitt lymphoma and provide the basis for new approaches to the treatment of this disease

Tasks of Provincial Road Managers – Safety and Convenience of Travelling

The maintenance of the appropriate condition of the road infrastructure, as well as the regularity of its management, significantly affect the improvement of safety and convenience of regional movement. In this context, the Supreme Audit Office conducted an audit of the activities of the road administrators in the Łódzkie, Małopolskie, Mazowieckie and Podlaskie Regions (these units managed 6,701.5 km of roads in total), and in the Municipal Road Administration (MZD) in Płock and in Warsaw. The audit covered the entities that manage ca. 23.6% of the regional roads in Poland

Toward stereocontrolled, chemoenzymatic synthesis of unnatural peptides

An efficient, chemoenzymatic method for the multicomponent synthesis of unnatural tripeptides is presented. Development of a previously described procedure combines the diversity offered by multicomponent reactions with the selectivity of biocatalysts and allows the convenient introduction of varied amino acid moieties into the tripeptide scaffold, with control of the stereochemistry. Additionally, it allows the introduction of a methyl group to the amide nitrogen, leading to derivatives of N-methylated amino acids. (c) 2008 Elsevier Ltd. All rights reserved

Chemoenzymatic synthesis of enantiomerically enriched alpha-hydroxyamides

A study on a chemoenzymatic synthesis of model alpha-hydroxyamide was performed. Special attention was paid to the optimization of the enzymatic process, both on the selection of enzyme and cosolvent. An intriguing influence of cosolvent on the enantioselectivity of Wheat Germ Lipase and Amano PS Lipase catalyzed hydrolysis was observed, as the results obtained proved that enzyme's enantioselectivity is directly correlated with cosolvent's hydrophobicity. In the best example (Wheat Germ lipase, Et2O used as a cosolvent), the reaction proceeded with E = 55, and the target compound was obtained in 33% yield with 92.7%ee. (c) 2007 Elsevier B.V. All rights reserved

Multicomponent diversity and enzymatic enantioselectivity as a route towards both enantiomers of alpha-amino acids:A model study

A model study on a new, enantioconvergent method for the synthesis of chiral, nonracemic alpha-amino acids is presented. alpha-Acetoxyamides obtained in a Passerini multicomponent reaction are selectively hydrolyzed by Wheat Germ lipase. Studies on conversion of the thus obtained, enantiomerically enriched alpha-hydroxyamides into alpha-aminoamides are presented. Products of these reactions are then hydrolyzed to give alpha-amino acids. (c) 2006 Elsevier Ltd. All rights reserved

Application of isocyanides derived from alpha-amino acids as substrates for the Ugi reaction

A systematic study on the influence of Lewis acid, solvent, and temperature on the stereochemical course of the Ugi reaction was performed to find conditions in which the isocyanides derived from enantiopure alpha-amino acids do not racemize. After a series of experiments, dichloromethane was used as a solvent and BF(3)center dot OEt(2) as a Lewis acid catalyst. This combination allowed us to obtain a product in a model reaction with 99% diastereoisomeric ratio (dr), with the structure motif of a group of cathepsin K inhibitors

Alpha-amino acids as acid components in the Passerini reaction: Influence of N-protection on the yield and stereoselectivity

The Passerini reaction offers an easy access to depsipeptides, when both acid and isocyanide are derived from of.-amino acids. However, racemisation of isocyanides derived from alpha-amino acid esters severely limits their use in the Passerini reaction. In order to overcome this limitation, a study on the influence of the alpha-amino acid N-protecting group on the yield and diastereoisomeric ratio of the product of the Passerini reaction was performed. Six different protecting groups were tested. Their influence turns out to be crucial and is not constant when the amino acid is changed. After optimisation, the Passerini reaction products with cyclohexanone as the carbonyl component were obtained with 99% yield and >98% de. (C) 2008 Elsevier Ltd. All rights reserved

Studies on the application of the Passerini reaction and enzymatic procedures to the synthesis of tripeptide mimetics

A new, efficient method for the multicomponent synthesis of tripeptide mimetics is presented. Simple, chemoenzymatic transformations of Passerini reaction products enable the introduction of varied amino acid moieties into the tripeptide scaffold, with control of the stereochemistry. Additionally, this method allows the convenient introduction of a methyl group to the amide nitrogen, leading to derivatives of N-methylated amino acids-compounds of interest for medicinal chemistry. (C) 2007 Elsevier Ltd. All rights reserved