Enantioselective Organocatalysis-Based Synthesis of 3-Hydroxy Fatty Acids and Fatty γ-Lactones.

3-Hydroxy fatty acids have attracted the interest of researchers, since some of them may interact with free fatty acid receptors more effectively than their non-hydroxylated counterparts and their determination in plasma provides diagnostic information regarding mitochondrial deficiency. We present here the development of a convenient and general methodology for the asymmetric synthesis of 3-hydroxy fatty acids. The enantioselective organocatalytic synthesis of terminal epoxides, starting from long chain aldehydes, is the key-step of our methodology, followed by ring opening with vinylmagnesium bromide. Ozonolysis and subsequent oxidation leads to the target products. MacMillan's third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, a route for the incorporation of deuterium on the carbon atom carrying the hydroxy group was developed allowing the synthesis of deuterated derivatives, which may be useful in biological studies and in mass spectrometry studies. In addition, the synthesis of fatty γ-lactones, corresponding to 4-hydroxy fatty acids, was also explored.

ß-Lactones: A Novel Class of Ca2+-Independent Phospholipase A2 (Group VIA iPLA2) Inhibitors with the Ability To Inhibit ß-Cell Apoptosis.

Ca2+-independent phospholipase A2 (GVIA iPLA2) has gained increasing interest recently as it has been recognized as a participant in biological processes underlying diabetes development and autoimmune-based neurological disorders. The development of potent GVIA iPLA2 inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA2 inhibitors based on the ß-lactone ring. This functionality in combination with a four-carbon chain carrying a phenyl group at position-3 and a linear propyl group at position-4 of the lactone ring confers excellent potency. trans-3-(4-Phenylbutyl)-4-propyloxetan-2-one (GK563) was identified as being the most potent GVIA iPLA2 inhibitor ever reported ( XI(50) 0.0000021, IC50 1 nM) and also one that is 22 000 times more active against GVIA iPLA2 than GIVA cPLA2. It was found to reduce ß-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.

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.

Microsomal prostaglandin E2 synthase-1 inhibitors: a patent review.

INTRODUCTION: Microsomal prostaglandin E2 synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) generation. It is strongly upregulated in inflamed tissues and overexpressed in tumors and it has been recognized as a key enzyme in inflammatory diseases such as arthritis, atherosclerosis, stroke and cancer. Thus, a great effort has been devoted in developing synthetic mPGES-1 inhibitors as novel anti-inflammatory agents. Areas covered: This review article summarizes the mPGES-1 inhibitors presented in patent literature from 2000 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo. Expert opinion: The side effects of NSAIDs and COX-2 inhibitors on the gastrointestinal tract and the cardiovascular system showcase the urgent need for the discovery of novel potent and safe anti-inflammatory drugs. mPGES-1 inhibitors may present superior safety in comparison to existing anti-inflammatory drugs. The first synthetic inhibitor of mPGES-1 was reported in 2001 and up to now a variety of structurally different inhibitors has been developed. However, only recently two inhibitors entered clinical trials and none has reached yet the market. More preclinical and clinical studies on mPGES-1 inhibitors are needed to realize if indeed they may become novel agents for the treatment of inflammation and cancer.

Autotaxin inhibitors: a patent review (2012-2016).

INTRODUCTION: Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. The ATX/LPA axis has received increasing interest in recent years because both the enzyme ATX and the bioactive lipid LPA are involved in various pathological conditions such as tumor progression and metastasis, fibrotic diseases, autoimmune diseases, arthritis, chronic hepatitis, obesity and impaired glucose homeostasis. Thus, a great effort has been devotd in developing synthetic ATX inhibitors as new agents to treat various diseases including cancer and fibrotic diseases. Areas covered: This review article summarizes the autotaxin inhibitors presented in patent literature from October 2012 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo. Expert opinion: During the recent years, there has been an intensive effort on the discovery of potent and selective ATX inhibitors. Although various synthetic inhibitors have been developed, only limited studies for their in vivo activity have been reported so far. A decade after the first claim of synthetic ATX inhibitors in 2006, one inhibitor has been in clinical trials for idiopapthic pulmonary fibrosis. The use of ATX inhibitors seems an attractive strategy to produce novel medicinal agents, for example anticancer agents.

Visible-Light-Mediated Catalytic Hydroacylation of Dialkyl Azodicarboxylates by Graphite Flakes.

A novel and efficient metal-free catalyzed hydroacylation of dialkyl azodicarboxylates is reported. Graphite flakes were found to be the most efficient catalyst among other carbon-based materials to promote this reaction. This unprecedented catalytic activity can be expanded into a wide substrate scope of aliphatic aldehydes bearing various functional groups, leading to the corresponding products in good to excellent yields.

Inhibitors of phospholipase A2 and their therapeutic potential: an update on patents (2012-2016).

INTRODUCTION: The regulation of the catalytic activity of the various phospholipase A2 enzymes is of high importance because these enzymes are involved in various pathological conditions such as arthritis, cardiovascular diseases, neurological diseases, and cancer. Thus, a great effort has been devoted in developing synthetic inhibitors as new agents to treat inflammatory diseases. Some of them have reached clinical trials. Areas covered: This review article discusses the phospholipase A2 inhibitors presented in patent literature from October 2012 to June 2016, their activities in vitro and in vivo as well as the results of clinical trials using synthetic PLA2 inhibitors. Expert opinion: None of the inhibitors studied in clinical trials have reached the market yet. The failure of lipoprotein-associated PLA2 inhibitor darapladib to reduce the risk of major coronary events suggests that this enzyme may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular diseases. These findings, together with the failure of secreted PLA2 inhibitor varespladib for the treatment of cardiovascular disease, indicate that deeper knowledge on these enzymes is needed. Inhibitors of cytosolic PLA2 are in clinical trials against psoriasis and atopic dermatitis.

Development of Potent and Selective Inhibitors for Group VIA Calcium-Independent Phospholipase A2 Guided by Molecular Dynamics and Structure-Activity Relationships.

The development of inhibitors for phospholipase A2 (PLA2) is important in elucidating the enzymes implication in various biological pathways. PLA2 enzymes are an important pharmacological target implicated in various inflammatory diseases. Computational chemistry, organic synthesis, and in vitro assays were employed to develop potent and selective inhibitors for group VIA calcium-independent PLA2. A set of fluoroketone inhibitors was studied for their binding mode with two human cytosolic PLA2 enzymes: group IVA cPLA2 and group VIA iPLA2. New compounds were synthesized and assayed toward three major PLA2s. This study led to the development of four potent and selective thioether fluoroketone inhibitors as well as a thioether keto-1,2,4-oxadiazole inhibitor for GVIA iPLA2, which will serve as lead compounds for future development and studies. The keto-1,2,4-oxadiazole functionality with a thioether is a novel structure, and it will be used as a lead to develop inhibitors with higher potency and selectivity toward GVIA iPLA2.

One-pot synthesis of O-allylhydroxylamines through the organocatalytic oxidation of tertiary allylic amines followed by a [2,3]-meisenheimer rearrangement.

A cheap, green, and highly efficient one-pot method for the synthesis of O-protected allylic alcohols is described. By utilizing 2,2,2-trifluoroacetophenone as the organocatalyst and H2 O2 as the oxidant, a variety of allylic amine N-oxides were synthesized, which upon heating are converted to the final products through a [2,3]-Meisenheimer rearrangement.

Photoorganocatalytic hydroacylation of dialkyl azodicarboxylates by utilising activated ketones as photocatalysts.

A fast and efficient visible-light metal-free hydroacylation of dialkyl azodicarboxylates is described. Among a variety of activated ketones, phenyl glyoxylic acid and its ethyl ester were identified as suitable photoorganocatalysts. A range of aliphatic and aromatic aldehydes were employed, thus leading to products in high to excellent yields.

2,2,2-Trifluoroacetophenone: an organocatalyst for an environmentally friendly epoxidation of alkenes.

A cheap, mild, fast, and environmentally friendly oxidation of olefins to the corresponding epoxides is reported using polyfluoroalkyl ketones as efficient organocatalysts. Namely, 2,2,2-trifluoroacetophenone was identified as an improved organocatalyst for the epoxidation of alkenes. Various olefins, mono-, di-, and trisubstituted, are epoxidized chemoselectively in high to quantitative yields utilizing 2-5 mol % catalyst loading and H2O2 as the green oxidant.

2,2,2-Trifluoroacetophenone as an organocatalyst for the oxidation of tertiary amines and azines to N-oxides.

A cheap, mild and environmentally friendly oxidation of tertiary amines and azines to the corresponding N-oxides is reported by using polyfluoroalkyl ketones as efficient organocatalysts. 2,2,2-Trifluoroacetophenone was identified as the optimum catalyst for the oxidation of aliphatic tertiary amines and azines. This oxidation is chemoselective and proceeds in high-to-quantitative yields utilizing 10 mol % of the catalyst and H2 O2 as the oxidant.

Novel pyrrolidine-thiohydantoins/thioxotetrahydropyrimidinones as highly effective catalysts for the asymmetric Michael addition.

The synthesis of novel organocatalysts consisting of a pyrrolidine moiety and a thiohydantoin or a thioxotetrahydropyrimidinone ring is described. The compound combining the pyrrolidine with the thioxotetrahydropyrimidinone was found to be a highly effective catalyst for the Michael reaction. Low catalyst loadings (1-2.5%) can be employed leading to quantitative yields and excellent stereoselectivities in the reaction between cyclic ketones and nitroolefins.