A tripeptide-like prolinamide-thiourea as an aldol reaction catalyst

A tripeptide-like prolinamide-thiourea catalyst with (S)-proline, (1S,2S)-diphenylethylenediamine and (S)-di-tert-butyl aspartate as building blocks provides the products of the reaction between ketones and aromatic aldehydes in high to quantitative yields and high stereoselectivities (up to 99 : 1 dr and 99% ee). Both the chiral centers of the diamine unit are essential, while the thiourea hydrogen originating from the amine and the amide hydrogen play a predominant role for the catalyst efficiency

Prolinamides carrying a thiourea group as new catalysts for the asymmetric aldol reaction

At the beginning of the 21st century, organocatalysis has emerged as a new powerful methodology for the synthesis of enantiopure organic compounds. The breakthrough of proline-catalyzed asymmetric direct aldol reaction together with the pioneering work on catalytic thioureas and imidazolidinones opened new directions in asymmetric catalysis. The five-membered secondary amine structure of proline is considered as a“privileged” structure able to activate carbonyl compounds through the formation of enamine intermediates. In an attempt to develop new organocatalysts, we thought of combining a thiourea group with prolinamide or an α-amino acid amide unit. Thiourea group is a well known double hydrogen bond donor and recently we have shown that chiral thioureas based on tert-butyl esters of α- amino acids are excellent catalysts for the asymmetric Michael reaction.1 In the present work, we describe the synthesis of various α-amino acid amides based on a chiral diamine carrying a thiourea group (general structure 1). The catalytic efficiency of the new organocatalysts was evaluated in the aldol reaction between acetone and 4-nitrobenzaldehyde. Prolinamide derivative was more efficient than the valinamide and the threonine amide derivatives. The catalyst based on (S)-proline and (1S,2S)-diphenylethylenediamine proved to be an excellent catalyst providing the products between ketones and aromatic aldehydes in high to quantitative yield and high stereoselectivitie

Tripeptide-Like prolinamide catalysts for the aldol reaction

Enzymes are the foundation upon which the majority of organocatalysts bearing more than one catalytic functionalities and act either by covalent or non-covalent interactions, has been developed. The proline and its derivatives containing bio-isosteric groups as replacements of the carboxylic group, constitute a good example of catalysts that bring out transformations as the aldol and Michael reaction succesfully, via bifunctional catalysis.1 Important improvement has been the development of catalysts combining a proline or proline derivative unit with additional functionalities able to act as hydrogen bond donors. Amide catalysts based on (S)-proline and (1S,2S)-1,2-diphenylethylenediamine or (1S,2S)-1,2-diphenyl-2-aminoethanol are representative examples featuring amine or hydroxyl group respectively, as the terminal donor group.2 These analogues provide the opportunity of introducing chiral substituents between donor groups and/or to the terminal heteroatom, thus enhancing the efficacy of the resulting catalyst. Furthemore, combination of additional chiral units, together with even more hydrogen bond donors, would mimic much better a “miniature active site”, providing therefore multifunctional organocatalysts. We have shown that prolinamide catalyst based on (1S,2S)- 1,2 diphenylethylenediamine and bears a double hydrogen bond donor thiourea group linked to a substituted aromatic ring, efficiently catalyze the aldol reaction between ketones and aromatic aldehydes in high to quantitative yields and with high stereoselectivities.3 Herein, we report a structure activity relationship study undertaken to identify the functional groups of the catalyst responsible for the activity resembling structure activity relationship studies to identify the pharmacophores of a lead bioactive compound. A tripeptide-like prolinamide-thiourea catalyst having as building blocks (S)-proline (1S,2S)-1,2-diphenylenediamine and (S)-di-tertbutyl aspartate provides the products of the aldol reaction in high to quantitative yields and in high stereoselectivities (up to 99:1 dr and 99% ee)

Fluoroketone inhibition of Ca(2+)-independent phospholipase A2 through binding pocket association defined by hydrogen/deuterium exchange and molecular dynamics.

The mechanism of inhibition of group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)) by fluoroketone (FK) ligands is examined by a combination of deuterium exchange mass spectrometry (DXMS) and molecular dynamics (MD). Models for iPLA(2) were built by homology with the known structure of patatin and equilibrated by extensive MD simulations. Empty pockets were identified during the simulations and studied for their ability to accommodate FK inhibitors. Ligand docking techniques showed that the potent inhibitor 1,1,1,3-tetrafluoro-7-phenylheptan-2-one (PHFK) forms favorable interactions inside an active-site pocket, where it blocks the entrance of phospholipid substrates. The polar fluoroketone headgroup is stabilized by hydrogen bonds with residues Gly486, Gly487, and Ser519. The nonpolar aliphatic chain and aromatic group are stabilized by hydrophobic contacts with Met544, Val548, Phe549, Leu560, and Ala640. The binding mode is supported by DXMS experiments showing an important decrease of deuteration in the contact regions in the presence of the inhibitor. The discovery of the precise binding mode of FK ligands to the iPLA(2) should greatly improve our ability to design new inhibitors with higher potency and selectivity

2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2.

Cytosolic phospholipase A2 (GIVA cPLA2) is the only PLA2 that exhibits a marked preference for hydrolysis of arachidonic acid containing phospholipid substrates releasing free arachidonic acid and lysophospholipids and giving rise to the generation of diverse lipid mediators involved in inflammatory conditions. Thus, the development of potent and selective GIVA cPLA2 inhibitors is of great importance. We have developed a novel class of such inhibitors based on the 2-oxoester functionality. This functionality in combination with a long aliphatic chain or a chain carrying an appropriate aromatic system, such as the biphenyl system, and a free carboxyl group leads to highly potent and selective GIVA cPLA2 inhibitors (X I(50) values 0.00007-0.00008) and docking studies aid in understanding this selectivity. A methyl 2-oxoester, with a short chain carrying a naphthalene ring, was found to preferentially inhibit the other major intracellular PLA2, the calcium-independent PLA2. In RAW264.7 macrophages, treatment with the most potent 2-oxoester GIVA cPLA2 inhibitor resulted in over 50% decrease in KLA-elicited prostaglandin D2 production. The novel, highly potent and selective GIVA cPLA2 inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of inflammatory diseases

Small Peptides Able to Suppress Prostaglandin E₂ Generation in Renal Mesangial Cells.

Peptide drug discovery may play a key role in the identification of novel medicinal agents. Here, we present the development of novel small peptides able to suppress the production of PGE₂ in mesangial cells. The new compounds were generated by structural alterations applied on GK115, a novel inhibitor of secreted phospholipase A₂, which has been previously shown to reduce PGE₂ synthesis in rat renal mesangial cells. Among the synthesized compounds, the tripeptide derivative 11 exhibited a nice dose-dependent suppression of PGE₂ production, similar to that observed for GK115

The Contribution of Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s to Adrenic Acid Mobilization in Murine Macrophages

Producción CientíficaAdrenic acid (AA), the 2-carbon elongation product of arachidonic acid, is present at significant levels in membrane phospholipids of mouse peritoneal macrophages. Despite its abundance and structural similarity to arachidonic acid, very little is known about the molecular mechanisms governing adrenic acid mobilization in cells of the innate immune system. This contrasts with the wide availability of data on arachidonic acid mobilization. In this work, we used mass-spectrometry-based lipidomic procedures to define the profiles of macrophage phospholipids that contain adrenic acid and their behavior during receptor activation. We identified the phospholipid sources from which adrenic acid is mobilized, and compared the data with arachidonic acid mobilization. Taking advantage of the use of selective inhibitors, we also showed that cytosolic group IVA phospholipase A2 is involved in the release of both adrenic and arachidonic acids. Importantly, calcium independent group VIA phospholipase A2 spared arachidonate-containing phospholipids and hydrolyzed only those that contain adrenic acid. These results identify separate mechanisms for regulating the utilization of adrenic and arachidonic acids, and suggest that the two fatty acids may serve non-redundant functions in cells.Ministerio de Economía, Industria y Competitividad (grant SAF2016-80883-R