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Prostaglandin E2 (PGE2 ) is a key mediator of inflammation, and consequently huge efforts have been devoted to the development of novel agents able to regulate its formation. In this work, we present the synthesis of various α-ketoheterocycles and a study of their ability to inhibit the formation of PGE2 at a cellular level. A series of α-ketobenzothiazoles, α-ketobenzoxazoles, α-ketobenzimidazoles, and α-keto-1,2,4-oxadiazoles were synthesized and chemically characterized. Evaluation of their ability to suppress the generation of PGE2 in interleukin-1β plus forskolinstimulated mesangial cells led to the identification of one α-ketobenzothiazole (GK181) and one α-ketobenzoxazole (GK491), which are able to suppress the PGE2 generation at a nanomolar level. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Hydroxamic acid derivatives constitute an interesting novel class of antitumor agents. Three of them, including vorinostat, are approved drugs for the treatment of malignancies, while several others are currently under clinical trials. In this work, we present new vorinostat analogs containing the benzoxazole ring as the cap group and various linkers. The benzoxazole-based analogs were synthesized starting either from 2-aminobenzoxazole, through conventional coupling, or from benzoxazole, through a metal-free oxidative amination. All the synthesized compounds were evaluated for their antiproliferative activity on three diverse human cancer cell lines (A549, Caco-2 and SF268), in comparison to vorinostat. Compound 12 (GK601), carrying a benzoxazole ring replacement for the phenyl ring of vorinostat, was the most potent inhibitor of the growth of three cell lines (IC50 1.2–2.1 μΜ), similar in potency to vorinostat. Compound 12 also inhibited human HDAC1, HDAC2 and HDAC6 like vorinostat. This new analog also showed antiproliferative activity against two colon cancer cell lines genetically resembling pseudomyxoma peritonei (PMP), namely HCT116 GNAS R201C/+ and LS174T (IC50 0.6 and 1.4 μΜ, respectively) with potency comparable to vorinostat (IC50 1.1 and 2.1 μΜ, respectively). © 2021 Elsevier Inc.

Oxidized saturated fatty acids, containing a hydroxyl or an oxo functionality, have attracted little attention so far. Recent studies have shown that saturated hydroxy fatty acids, which exhibit cancer cell growth inhibition and may suppress β-cell apoptosis, are present in milk. Herein, we present the application of a liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method for the detection and quantification of various saturated oxo fatty acids (SOFAs) previously unrecog-nized in milk. This robust and rapid analytical method, which involves simple sample preparation and a single 10-min run, revealed the presence of families of oxostearic acids (OSAs) and oxopalmitic acids (OPAs) in milk. 8OSA, 9OSA, 7OSA, 10OSA and 10OPA were found to be the most abundant SOFAs in both cow and goat milk. Higher contents of SOFAs were found in cow milk in comparison to goat milk. Together with SOFAs, ricinoleic acid, which is isobaric to OSA, was detected and quan-tified in all milk samples, following a “suspect” HRMS analysis approach. This unique natural fatty acid, which is the main component (>90%) of castor oil triglycerides, was estimated at mean content values of 534.3 ± 6.0 µg/mL and 460 ± 8.1 µg/mL in cow and goat milk samples, respectively. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Phospholipase A2 (PLA2) enzymes are implicated in several pathological conditions such as arthritis, cardiovascular diseases, and diabetes. It is highly important to regulate their activity and develop PLA2 inhibitors as new agents to treat inflammatory diseases. Areas covered: This review article summarizes the most important synthetic PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated Lp-PLA2), discussing their in vitro and in vivo activities as well as their recent applications and therapeutic properties. Recent findings on the role of PLA2 in the pathobiology of COVID-19 are also discussed. Expert opinion: Although a number of PLA2 inhibitors have entered clinical trials, none has reached the market yet. Lipoprotein-associated PLA2 is now considered a biomarker of vascular inflammation rather than a therapeutic target for inhibitors like darapladib. Inhibitors of cytosolic PLA2 may find topical applications for diseases like atopic dermatitis and psoriasis. Inhibitors of secreted PLA2, varespladib and varespladib methyl, are under investigation for repositioning in snakebite envenoming. A deeper understanding of PLA2 enzymes is needed for the development of novel selective inhibitors. Lipidomic technologies combined with medicinal chemistry approaches may be useful tools toward this goal. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

During biological events, the water molecules associated with the protein are re-oriented to adapt to the new conditions, inducing changes in the system’s free energy. The characterization of water structure and thermodynamics may facilitate the prediction of certain biological events, such as the binding of a ligand and the membrane-associated parts of a protein. In this computational study, we calculated the hydration thermodynamics of cytosolic phospholipase A2 group IV (GIVA cPLA2) to study the hydration properties of the protein’s surface and binding pocket. Hydrophobicity scales and the Grid Inhomogeneous Solvation Theory (GIST) tool were employed for the calculations. The hydrophobic areas of the protein’s surface were predicted more accurately with the GIST method rather than with the hydrophobicity scales. Based on this, a model of the protein-membrane complex was constructed. In addition, the calculation revealed the highly hydrated binding pocket that further contribute to our understanding of the ligands’ binding. Communicated by Ramaswamy H. Sarma. © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Unsaturated nitro fatty acids (NO2 -FAs) constitute a category of molecules that may be formed endogenously by the reaction of unsaturated fatty acids (UFAs) with secondary species of nitrogen monoxide and nitrite anions. The warhead of NO2 -FAs is a nitroalkene moiety, which is a potent Michael acceptor and can undergo nucleophilic attack from thiol groups of biologically relevant proteins, showcasing the value of these molecules regarding their therapeutic potential against many diseases. In general, NO2 -FAs inhibit nuclear factorκ-B (NF-κB), and simultaneously they activate nuclear factor (erythroid derived)-like 2 (Nrf2), which activates an antioxidant signaling pathway. NO2 -FAs can be synthesized not only endogenously in the organism, but in a synthetic laboratory as well, either by a step-by-step synthesis or by a direct nitration of UFAs. The step-by-step synthesis requires specific precursor compounds and is in position to afford the desired NO2 -FAs with a certain position of the nitro group. On the contrary, the direct nitration of UFAs is not a selective methodology; thus, it affords a mixture of all possible nitro isomers. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

The determination of free fatty acids (FFAs) in milk is of importance for quality control, legislative purposes, authentication and product development. We present herein a liquid chromatography-high resolution mass spectrometry method for the direct determination of FFAs in milk. The method involves mild sample preparation, avoids time-consuming derivatization and allows the direct quantification of twenty-two FFAs in a 10-min single run. It was validated and applied in thirteen cow milk and seven goat milk samples. Saturated fatty acids C16:0, C18:0 and unsaturated C18:1 (n-9) were found to be the major components of milk FFAs at concentrations of 33.1 ± 8.2 µg/mL, 16.5 ± 5.3 µg/mL and 14.8 ± 3.8 µg/mL, respectively, in cow milk and at concentrations of 22.8 ± 1.8 µg/mL, 12.7 ± 2.8 µg/mL and 13.3 ± 0.3 µg/mL, respectively, in goat milk. Other saturated and unsaturated FFAs were found in significantly lower quantities. Saturated fatty acids C6:0, C8:0 and C10:0 were found in higher quantities in goat milk than in cow milk. The levels of the important (for human health) odd-chain FFAs C15:0 and C17:0 were estimated in cow and goat milk. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

The field of bioactive lipids is ever expanding with discoveries of novel lipid molecules that promote human health. Adopting a lipidomic-Assisted approach, two new families of previously unrecognized saturated hydroxy fatty acids (SHFAs), namely, hydroxystearic and hydroxypalmitic acids, consisting of isomers with the hydroxyl group at different positions, were identified in milk. Among the various regio-isomers synthesized, those carrying the hydroxyl at the 7-and 9-positions presented growth inhibitory activities against various human cancer cell lines, including A549, Caco-2, and SF268 cells. In addition, 7-and 9-hydroxystearic acids were able to suppress β-cell apoptosis induced by proinflammatory cytokines, increasing the possibility that they can be beneficial in countering autoimmune diseases, such as type 1 diabetes. 7-(R)-Hydroxystearic acid exhibited the highest potency both in cell growth inhibition and in suppressing β-cell death. We propose that such naturally occurring SHFAs may play a role in the promotion and protection of human health. © 2020 American Chemical Society. All rights reserved.

A liquid chromatography–high resolution mass spectrometry (LC-HRMS) method for the direct determination of various saturated hydroxy fatty acids (HFAs) in milk was developed for the first time. The method involves mild sample preparation conditions, avoids time-consuming derivatization procedures, and permits the simultaneous determination of 19 free HFAs in a single 10-min run. This method was validated and applied in 17 cow milk and 12 goat milk samples. This work revealed the existence of various previously unrecognized hydroxylated positional isomers of palmitic acid and stearic acid in both cow and goat milk, expanding our knowledge on the lipidome of milk. The most abundant free HFAs in cow milk were proven to be 7-hydroxystearic acid (7HSA) and 10-hydroxystearic acid (10HSA) (mean content values of 175.1 ± 3.4 µg/mL and 72.4 ± 6.1 µg/mL in fresh milk, respectively). The contents of 7HSA in cow milk seem to be substantially higher than those in goat milk. © 2020 by the authors.

2-Oxoesters constitute an important class of potent and selective inhibitors of human cytosolic phospholipase A2 (GIVA cPLA2) combining an aromatic scaffold or a long aliphatic chain with a short aliphatic chain containing a free carboxylic acid. Although highly potent 2-oxoester inhibitors of GIVA cPLA2 have been developed, their rapid degradation in human plasma limits their pharmaceutical utility. In an effort to address this problem, we designed and synthesized two new 2-oxoesters introducing a methyl group either on the α-carbon to the oxoester functionality or on the carbon carrying the ester oxygen. We studied the in vitro plasma stability of both derivatives and their in vitro inhibitory activity on GIVA cPLA2. Both derivatives exhibited higher plasma stability in comparison with the unsubstituted compound and both derivatives inhibited GIVA cPLA2, however to different degrees. The 2-oxoester containing a methyl group on the α-carbon atom to the oxoester functionality exhibits enhancement of the metabolic stability and retains considerable inhibitory potency. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

The corticotropin-releasing factor (CRF) and its CRF1 receptor (CRF1R) play a central role in the maintenance of homeostasis. Malfunctioning of the CRF/CRF1R unit is associated with several disorders, such as anxiety and depression. Non-peptide CRF1R-selective antagonists have been shown to exert anxiolytic and antidepressant effects on experimental animals. However, none of them is in clinical use today because of several side effects, thus demonstrating the need for the development of other more suitable CRF1R antagonists. In an effort to develop novel CRF1R antagonists we designed, synthesized and chemically characterized two tripeptide analogues of CRF, namely (R)-LMI and (S)-LMI, having their Leu either in R (or D) or in S (or L) configuration, respectively. Their design was based on the crystal structure of the N-extracellular domain (N-domain) of CRF1R/CRF complex, using a relevant array of computational methods. Experimental evaluation of the stability of synthetic peptides in human plasma has revealed that (R)-LMI is proteolytically more stable than (S)-LMI. Based on this finding, (R)-LMI was selected for pharmacological characterization. We have found that (R)-LMI is a CRF antagonist, inhibiting (1) the CRF-stimulated accumulation of cAMP in HEK 293 cells expressing the CRF1R, (2) the production of interleukins by adipocytes and (3) the proliferation rate of RAW 264.7 cells. (R)-LMI likely blocked agonist actions by interacting with the N-domain of CRF1R as suggested by data using a constitutively active chimera of CRF1R. We propose that (R)-LMI can be used as an optimal lead compound in the rational design of novel CRF antagonists. © 2020, Springer-Verlag GmbH Austria, part of Springer Nature.

Parkinson's disease is biochemically characterized by the deposition of aberrant aggregated α-synuclein in the affected neurons. The aggregation properties of α-synuclein greatly depend on its affinity to bind cellular membranes via a dynamic interaction with specific lipid moieties. In particular, α-synuclein can interact with arachidonic acid (AA), a polyunsaturated fatty acid, in a manner that promotes the formation of α-helix enriched assemblies. In a cellular context, AA is released from membrane phospholipids by phospholipase A2 (PLA2). To investigate the impact of PLA2 activity on α-synuclein aggregation, we have applied selective PLA2 inhibitors to a SH-SY5Y cellular model where the expression of human wild-type α-synuclein is correlated with a gradual accumulation of soluble oligomers and subsequent cell death. We have found that pharmacological and genetic inhibition of GIVA cPLA2 resulted in a dramatic decrease of intracellular oligomeric and monomeric α-synuclein significantly promoting cell survival. Our data suggest that alterations in the levels of free fatty acids, and especially AA and adrenic acid, promote the formation of α-synuclein conformers which are more susceptible to proteasomal degradation. This mechanism is active only in living cells and is generic since it does not depend on the absolute quantity of α-synuclein, the presence of disease-linked point mutations, the expression system or the type of cells. Our findings indicate that the α-synuclein-fatty acid interaction can be a critical determinant of the conformation and fate of α-synuclein in the cell interior and, as such, cPLA2 inhibitors could serve to alleviate the intracellular, potentially pathological, α-synuclein burden. © 2020 Federation of American Societies for Experimental Biology

Autotaxin (ATX), a glycoprotein (~125 kDa) isolated as an autocrine motility factor from melanoma cells, belongs to a seven-membered family of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP), and exhibits lysophospholipase D activity. ATX is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA), which is upregulated in a variety of pathological inflammatory conditions, including fibrosis, cancer, liver toxicity and thrombosis. Given its role in human disease, the ATX-LPA axis is an interesting target for therapy, and the development of novel potent ATX inhibitors is of great importance. In the present work a novel class of ATX inhibitors, optically active derivatives of 2-pyrrolidinone and pyrrolidine heterocycles were synthesized. Some of them exhibited interesting in vitro activity, namely the hydroxamic acid 16 (IC50 700 nM) and the carboxylic acid 40b (IC50 800 nM), while the boronic acid derivatives 3k (IC50 50 nM), 3l (IC50 120 nM), 3 m (IC50 180 nM) and 21 (IC50 35 nM) were found to be potent inhibitors of ATX. © 2019 Elsevier Ltd

The lipidome of royal jelly (RJ) consists of medium‐chained (8–12 carbon atoms) free fatty acids. We present herein a liquid chromatography‐high resolution mass spectrometry (HRMS) method that permits the determination of RJ fatty acids and at the same time the detection of suspect fatty acids. The method allows for the direct quantification of seven free fatty acids of RJ, avoiding any derivatization step. It was validated and applied in seven RJ samples, where the major RJ fatty acid trans‐10‐hydroxy‐2‐decenoic acid (10‐HDA) was found to vary from 0.771 ± 0.08 to 0.928 ± 0.04 g/100 g fresh RJ. Four additional suspect fatty acids were simultaneously detected taking advantage of the HRMS detection. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Type 1 diabetes (T1D) is a consequence of autoimmune β cell destruction, but the role of lipids in this process is unknown. We previously reported that activation of Ca2+-independent phospholipase A2β (iPLA2β) modulates polarization of macrophages (MΦ). Hydrolysis of the sn-2 substituent of glycerophospholipids by iPLA2β can lead to the generation of oxidized lipids (eicosanoids), pro- and antiinflammatory, which can initiate and amplify immune responses triggering β cell death. As MΦ are early triggers of immune responses in islets, we examined the impact of iPLA2βderived lipids (iDLs) in spontaneous-T1D prone nonobese diabetic mice (NOD), in the context of MΦ production and plasma abundances of eicosanoids and sphingolipids. We find that (a) MΦNOD exhibit a proinflammatory lipid landscape during the prediabetic phase; (b) early inhibition or genetic reduction of iPLA2β reduces production of select proinflammatory lipids, promotes antiinflammatory MΦ phenotype, and reduces T1D incidence; (c) such lipid changes are reflected in NOD plasma during the prediabetic phase and at T1D onset; and (d) importantly, similar lipid signatures are evidenced in plasma of human subjects at high risk for developing T1D. These findings suggest that iDLs contribute to T1D onset and identify select lipids that could be targeted for therapeutics and, in conjunction with autoantibodies, serve as early biomarkers of pre-T1D. Copyright: © 2020, Nelson et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Adrenic 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. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Phospholipase A2 (PLA2) enzymes are involved in various inflammatory pathological conditions including arthritis, cardiovascular and autoimmune diseases. The regulation of their catalytic activity is of high importance and a great effort has been devoted in developing synthetic inhibitors. We summarize the most important small-molecule synthetic PLA2 inhibitors developed to target each one of the four major types of human PLA2 (cytosolic cPLA2, calcium-independent iPLA2, secreted sPLA2, and lipoprotein-associated LpPLA2). We discuss recent applications of inhibitors to understand the role of each PLA2 type and their therapeutic potential. Potent and selective PLA2 inhibitors have been developed. Although some of them have been evaluated in clinical trials, none reached the market yet. Apart from their importance as potential medicinal agents, PLA2 inhibitors are excellent tools to unveil the role that each PLA2 type plays in cells and in vivo. Modern medicinal chemistry approaches are expected to generate improved PLA2 inhibitors as new agents to treat inflammatory diseases. © 2018 Elsevier B.V.

Ca 2+ -independent phospholipase A 2 (GVIA iPLA 2 ) 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 iPLA 2 inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA 2 inhibitors based on the β-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 iPLA 2 inhibitor ever reported (X I (50) 0.0000021, IC 50 1 nM) and also one that is 22 000 times more active against GVIA iPLA 2 than GIVA cPLA 2 . It was found to reduce β-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes. © 2019 American Chemical Society.

M. G. Kokotou's Post-Doctoral Research was implemented under IKY scholarship funded by the “Supporting Post-Doctoral Researchers” Action of the Operational Programme “Human Resources Development, Education and Lifelong Learning” with priority axes 6,8,9 and co-funded by the European Social Fund (ESF) and Greek National Resources. To replace: M.G.K. would like to thank the National Scholarship Foundation (IKY) for a fellowship. The authors would like to apologise for any inconvenience caused. © 2018 Elsevier B.V.

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. © 2019 by the authors

Availability of free arachidonic acid (AA) constitutes a rate limiting factor for cellular eicosanoid synthesis. AA distributes differentially across membrane phospholipids, which is largely due to the action of coenzyme A-independent transacylase (CoA-IT), an enzyme that moves the fatty acid primarily from diacyl phospholipid species to ether-containing species, particularly the ethanolamine plasmalogens. In this work, we examined the dependence of AA remodeling on plasmalogen content using the murine macrophage cell line RAW264.7 and its plasmalogen-deficient variants RAW.12 and RAW.108. All three strains remodeled AA between phospholipids with similar magnitude and kinetics, thus demonstrating that cellular plasmalogen content does not influence the process. Cell stimulation with yeast-derived zymosan also had no effect on AA remodeling, but incubating the cells in AA-rich media markedly slowed down the process. Further, knockdown of cytosolic-group IVC phospholipase A2γ (cPLA2γ) by RNA silencing significantly reduced AA remodeling, while inhibition of other major phospholipase A2 forms such as cytosolic phospholipase A2α, calcium-independent phospholipase A2β, or secreted phospholipase A2 had no effect. These results uncover new regulatory features of CoA-IT-mediated transacylation reactions in cellular AA homeostasis and suggest a hitherto unrecognized role for cPLA2γ in maintaining membrane phospholipid composition via regulation of AA remodeling.

The recent discovery of a novel class of endogenous lipids, named Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs), that present antidiabetic and anti-inflammatory activities, has attracted the interest on hydroxy fatty acids (HFAs) and their derivatives. We present herein the development of a convenient and general methodology for the asymmetric synthesis of HFAs and FAHFAs. The enantioselective organocatalytic synthesis of asymmetric terminal epoxides starting from monoprotected α,ω-diols and their subsequent ring opening by a Grignard reagent are the key-steps for our methodology, allowing the introduction of the hydroxy group at different positions of the long chain by proper selection of the starting diol and the Grignard reagent. MacMillan's third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, an approach for the synthesis of deuterated HFAs and FAHFAs was developed, leading to deuterated derivatives, which can be useful in biological studies and in mass spectrometry studies as internal standards. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Cytosolic phospholipase A2 (GIVA cPLA2) has attracted great interest as a medicinal target because it initiates the eicosanoid cascade and is involved in a number of inflammatory diseases. As a consequence, the development of potent synthetic inhibitors is of great importance. We have developed highly potent 2-oxoester inhibitors of GIVA cPLA2 presenting XI(50) values between 0.000019 and 0.000066. We demonstrate that the 2-oxoester functionality is essential for in vitro inhibitory activity, making these inhibitors useful research reagents. However, their high reactivity results in rapid degradation of the inhibitors in human plasma, limiting their pharmaceutical utility without further modification. © 2018 American Chemical Society.

Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) generating the lipid mediator lysophosphatidic acid (LPA). Both ATX and LPA are involved in various pathological inflammatory conditions, including fibrosis and cancer, and have attracted great interest as medicinal targets over the past decade. Thus, the development of novel potent ATX inhibitors is of great importance. We have developed a novel class of ATX inhibitors containing the zinc binding functionality of hydroxamic acid. Such novel hydroxamic acids that incorporate a non-natural δ-amino acid residue exhibit high in vitro inhibitory potency over ATX (IC 50 values 50-60 nM). Inhibitor 32, based on δ-norleucine, was tested for its efficacy in a mouse model of pulmonary inflammation and fibrosis induced by bleomycin and exhibited promising efficacy. The novel hydroxamic ATX 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 fibrosis and other chronic inflammatory diseases. © 2018 American Chemical Society.

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. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

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. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

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. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Calcium-independent phospholipase A2(GVIA iPLA2) has recently attracted interest as a medicinal target. The number of known GVIA iPLA2inhibitors is limited to a handful of synthetic compounds (bromoenol lactone and polyfluoroketones). To expand the chemical diversity, a variety of 2-oxoamides based on dipeptides and ether dipeptides were synthesized and studied for their in vitro inhibitory activity on human GVIA iPLA2and their selectivity over the other major intracellular GIVA cPLA2and the secreted GV sPLA2. Structure-activity relationship studies revealed the first 2-oxoamide derivative (GK317), which presents potent inhibition of GVIA iPLA2(XI(50) value of 0.007) and at the same time significant selectivity over GIVA cPLA2and GV sPLA2. © 2016 Elsevier Ltd

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. © 2016 American Chemical Society.

Hydroxymethyl ketones are useful auxiliaries in organic synthesis and are also found in several medicinal agents. N-Heterocyclic carbenes (NHCs) have been used in the literature in order to introduce the hydroxymethyl group into aromatic aldehydes in good yields, but they are not that successful for aliphatic aldehydes. In the present work, the use of microwave irradiation has been efficiently incorporated into this organocatalytic synthesis of aromatic, but more importantly of aliphatic hydroxymethyl ketones that can be used as precursors for medicinally interesting compounds. © 2016 Elsevier Ltd

Phospholipase A2 (PLA2) activity has been shown to be involved in the sperm acrosome reaction (AR), but the molecular identity of PL A2 isoforms has remained elusive. Here, we have tested the role of two intracellular (iPL A2 β and cytosolic PL A2 α) and one secreted (group X) PLA2s in spontaneous and progesterone (P4)-induced AR by using a set of specific inhibitors and knock-out mice. iPL A2β is critical for spontaneous AR, whereas both iPL A2 β and groupXsecreted PL A2 are involved in P4-induced AR. Cytosolic PL A2 α is dispensable in both types of AR. P4-induced AR spreads over 30 min in the mouse, and kinetic analyses suggest the presence of different sperm subpopulations, using distinctPL A2 pathways to achieve AR. At low P4 concentration (2M), sperm undergoing early AR (0-5 min post-P4) rely on iPL A2 β , whereas sperm undergoing late AR (20-30 min post-P4) rely on group X secreted PL A2. Moreover, the role of PL A2 s in AR depends on P4 concentration, with the PLA2s being key actors at low physiological P4 concentrations (

The upregulation of PGE2 by mesangial cells has been observed under chronic inflammation condition. In the present work, renal mesangial cells were stimulated to trigger a huge increase of PGE2 synthesis and were treated in the absence or presence of known PLA2 inhibitors. A variety of synthetic inhibitors, mainly developed in our labs, which are known to selectively inhibit each of GIVA cPLA2, GVIA iPLA2, and GIIA/GV sPLA2, were used as tools in this study. Synthetic sPLA2 inhibitors, such as GK115 (an amide derivative based on the non-natural amino acid (R)-γ-norleucine) as well as GK126 and GK241 (2-oxoamides based on the natural (S)-α-amino acid leucine and valine, respectively) presented an interesting effect on the suppression of PGE2 formation. © 2016 Elsevier Ltd. All rights reserved.

Cytosolic GIVA phospholipase A2(GIVA cPLA2) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA2inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA2. Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048. © 2016 Elsevier Ltd

Phospholipases A2 (PLA2) are a diverse group of enzymes that hydrolyze membrane phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is metabolized to eicosanoids (prostaglandins, leukotrienes, thromboxanes), and lysophospholipids are converted to platelet-activating factors. These lipid mediators play critical roles in the initiation, maintenance, and modulation of neuroinflammation and oxidative stress. Neurological disorders including excitotoxicity; traumatic nerve and brain injury; cerebral ischemia; Alzheimers disease; Parkinsons disease; multiple sclerosis; experimental allergic encephalitis; pain; depression; bipolar disorder; schizophrenia; and autism are characterized by oxidative stress, inflammatory reactions, alterations in phospholipid metabolism, accumulation of lipid peroxides, and increased activities of brain phospholipase A2 isoforms. Several old and new synthetic inhibitors of PLA2, including fatty acid trifluoromethyl ketones; methyl arachidonyl fluorophosphonate; bromoenol lactone; indole-based inhibitors; pyrrolidine-based inhibitors; amide inhibitors, 2-oxoamides; 1,3-disubstituted propan-2-ones and polyfluoroalkyl ketones as well as phytochemical based PLA2 inhibitors including curcumin, Ginkgo biloba and Centella asiatica extracts have been discovered and used for the treatment of neurological disorders in cell culture and animal model systems. The purpose of this review is to summarize information on selective and potent synthetic inhibitors of PLA2 as well as several PLA2 inhibitors from plants, for treatment of oxidative stress and neuroinflammation associated with the pathogenesis of neurological disorders. © 2015 American Chemical Society.