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Pollution and the rising energy demand have prompted the design of new synthetic reactions that meet the principles of green chemistry. In particular, alternative synthesis of 2-aminothiophene have recently focused interest because 2-aminothiophene is a unique 5-membered S-heterocycle and a pharmacophore providing antiprotozoal, antiproliferative, antiviral, antibacterial or antifungal properties. Here, we review new synthetic routes to 2-aminothiophenes, including multicomponent reactions, homogeneously- or heterogeneously-catalyzed reactions, with focus on green pathways.

The loss of pancreatic β-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cell-autonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of β-cell identity, insulin secretion and glucose homeostasis. We show that the β-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, an altered endocrine cell mass, a downregulation of many β-cell genes and a concomitant increase of non-β-cell markers. Mechanistically, the epigenomic profiling of promoters of these non-β-cell upregulated genes identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, promoters of downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that specific E2f1 transcriptional, cistromic and epigenomic signatures are associated with these β-cell dysfunctions, with E2F1 directly regulating several β-cell genes at the chromatin level. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of β-cell identity genes. Our data suggest that E2F1 is critical for maintaining β-cell identity and function through a sustained control of β-cell and non β-cell transcriptional programs.

The loss of pancreatic β-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cellautonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of β-cell identity, insulin secretion and glucose homeostasis. We show that the β-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, an altered endocrine cell mass, a downregulation of many β-cell genes and a concomitant increase of non-β-cell markers. Mechanistically, the epigenomic profiling of promoters of these non-β-cell upregulated genes identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, promoters of downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that specific E2f1 transcriptional, cistromic and epigenomic signatures are associated with these β-cell dysfunctions, with E2F1 directly regulating several β-cell genes at the chromatin level. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of β-cell identity genes. Our data suggest that E2F1 is critical for maintaining β-cell identity and function through a sustained control of β-cell and non β-cell transcriptional programs.

Plants are an everlasting inspiration source of biologically active compounds. Among these medicinal plants, the biological activity of extracts from some species of the

Infections caused by multidrug-resistant bacteria represent a significant and ever-increasing cause of morbidity and mortality. There is thus an urgent need to develop efficient and well-tolerated antibacterials targeting unique cellular processes. Numerous studies have led to the identification of new biological targets to fight bacterial resistance. Two-component signal transduction systems are widely employed by bacteria to translate external and cellular signals into a cellular response. They are ubiquitous in bacteria, absent in the animal kingdom and are integrated into various virulence pathways. Several chemical series, including isothiazolidones, imidazolium salts, benzoxazines, salicylanilides, thiophenes, thiazolidiones, benzimidazoles and other derivatives deduced by different approaches have been reported in the literature to have histidine kinase inhibitory activity. In this review, we report on the design and the synthesis of these histidine kinases inhibitors and their potential to serve as antibacterial agents.

The glucagon-like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential in type 2 diabetes (T2D) treatment, notably by improving β cell functions. The cell-cycle regulator and transcription factor E2f1 is involved in glucose homeostasis by modulating β cell mass and function. Here, we report that β cell-specific genetic ablation of E2f1 (E2f1

Compromised β-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving β-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating β-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that β-cell specificE2f1deficient mice (E2f1β−/−) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 (i.e., GLP1R agonist), which were associated with decreased expression ofGlp1rencoding Glp-1 receptor (GLP1R) inE2f1β−/−pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreasedGLP1Rlevels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressingE2f1in pancreatic β cells increasedGlp1rexpression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.

In medicinal chemistry, 2-aminothiophene is a central five-membered heterocyclic core that is mostly synthesized using Gewald methodology. Its incorporation into a molecule can confer broad biological activities, making 2-aminothiophene an attractive scaffold for drug discovery. Another interesting feature of 2-aminothiophene moiety is its ability to act as synthon for the synthesis of biological active thiophene-containing heterocycles, conjugates or hybrids. Compounds from the 2-aminothiophene family are promising selective inhibitors and modulators in medicinal chemistry, and even exhibit effective pharmacological properties in the various clinical phases of appropriate diseases. Likewise, the biological actions of 2-aminothiophenes or their 2-N-substituted analogs are still being investigated because of their diverse mechanisms of action (e.g., pharmacophore and pharmacokinetic properties). In this review, we focus on the structure-activity relationship, the synthesis and the biological activities of 2-aminothiophene derivatives, including antiprotozoal, antiproliferative, antiviral, antibacterial, antifungal, channel and cannabinoid receptor inhibitors. Most perspective drug-candidate hits were selected for discussion and described, along with additional synthetic pathways. Since there has been several contributions in this field recently, we emphasized on the literature dedicated to 2-aminothiophenes and 2-N-substituted derivatives which have been published from 2017 to 2022.

The loss of pancreatic β-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cell-autonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of β-cell identity and insulin secretion. We show that the β-cell-specific loss ofE2f1function in mice triggers glucose intolerance associated with defective insulin secretion, an altered α-to-β-cell ratio, a downregulation of many β-cell genes and a concomitant increase of non-β-cell markers. Mechanistically, the epigenomic profiling of non-beta cell upregulated gene promoters identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that histone deacetylase inhibitors modulate E2F1 transcriptional and epigenomic signatures associated with these β-cell dysfunctions. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of β-cell identity genes. Our data suggest that E2F1 is critical for maintaining β-cell identity through a sustained repression of non β-cell transcriptional programs.

International audience; The ethynylglycine synthon {(R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyl-oxazolidine} is a chiral compound withvaluable synthetic interest. An update (covering literature from 2005 to 2017) on the different synthetic utilities is reviewedand discussed.

International audience

International audience; The emergence of multidrug-resistant bacteria emphasizes the urgent need for novel antibacterial compounds targeting unique cellular processes. Two-component signal transduction systems (TCSs) are commonly used by bacteria to couple environmental stimuli to adaptive responses, are absent in mammals, and are embedded in various pathogenic pathways. To attenuate these signaling pathways, we aimed to target the TCS signal transducer histidine kinase (HK) by focusing on their highly conserved adenosine triphosphate-binding domain. We used a structure-based drug design strategy that begins from an inhibitor-bound crystal structure and includes a significant number of structurally simplifiying “intuitive” modifications to arrive at the simple achiral, biaryl target structures. Thus, ligands were designed, leading to a series of thiophene derivatives. These compounds were synthesized and evaluated in vitro against bacterial HKs. We identified eight compounds with significant inhibitory activities against these proteins, two of which exhibited broad-spectrum antimicrobial activity. The compounds were also evaluated as adjuvants for the treatment of resistant bacteria. One compound was found to restore the sensivity of these bacteria to the respective antibiotics.

International audience; An improved green synthesis of the E2F inhibitor HLM0066474 is described, using solvent-free and microwave irradiation conditions. The two enantiomers are separated using semi-preparative separation on Chiralpak ID and their absolute configuration is determined by vibrational circular dichroism (VCD) analysis. Biological evaluation of both enantiomers on E2F1 transcriptional activity reveals that the (+)-R, but not the (−)-S enantiomer is biologically active in repressing E2F1 transcriptional activity.

International audience

International audience; Racemic-protected α-ethynylphenylalanine was synthesized from dl-2-benzylserine using α-benzylserinal as key intermediate and was uccessfully resolved by HPLC on a chiral stationary phase at a semipreparative scale. The absolute configuration of both enantiomers was determined by vibrational circular dichroism.

International audience; At present, some triazine herbicides occurrence in European groundwater, 13 years after their use ban in the European Union, remains of great concern and raises the question of their persistence in groundwater systems due to several factors such as storage and remobilization from soil and unsaturated zone, limited or absence of degradation, sorption insaturated zones, or to continuing illegal applications. In order to address this problem and to determine triazine distribution in the saturated zone, their occurrence is investigated in the light of the aquifer hydrodynamic on the basis of a geochemical approach using groundwater dating tracers (3H/3He). In this study, atrazine, simazine, terbuthylazine, deethylatrazine, deisopropylatrazine, and deethylterbuthylazine are measured in 66 samples collected between 2011 and 2013 from 21 sampling points, on the Vistrenque shallow alluvial aquifer (southern France), covered by a major agricultural land use. The frequencies of quantification range from 100 to 56 % for simazine and atrazine, respectively (LQ = 1 ng L−1). Total triazine concentrations vary between 15 and 350 ng L−1 and show three different patterns with depth below the water table : (1) low concentrations independent of depth but related to water origin, (2) an increase in concentrations with depth in the aquifer related to groundwater residence time and triazine use prior to their ban, and (3) relatively high concentrations at low depths in the saturated zone more likely related to a slow desorption of these compounds from the soil and unsaturated zone. The triazine attenuation rate varies between 0.3 for waters influenced by surface water infiltration and 4.8 for water showing longer residence times in the aquifer, suggesting an increase in these rates with water residence time in the saturated zone. Increasing triazine concentrations with depth is consistent with a significant decrease in the use of these pesticides for the last 10 years on this area and highlights the efficiency of their ban.

International audience; The diastereoselective synthesis of cis-5-trifluoromethylproline (5-Tfm-Pro) from l-glutamic acid is described. 5-Tfm-Pro could be obtained through a seven-step linear sequence. Trifluoromethylation of the glutamic-derived ester or aldehyde and subsequent reduction of the cyclic imine are the key steps in the synthesis.

Background: Tyrosine kinases (TK) are enzymes that catalyze the phosphorylation of tyrosine residues on proteins by the transfer of phosphate moiety of ATP. TK are key regulators of various cell functions, such as cellular growth, proliferation, migration, differentiation, and apoptosis. Src mutations and/or overexpression has been correlated with tumor growth, metastasis, and angiogenesis [4,5]. Thus, the design and the discovery of novel Src kinase inhibitors remains critically important. Methods: A series of 1,4-disubstituted 1,2,3-triazoles derivatives were designed and prepared as potential inhibitors for Src kinase. In this manuscript, all of the designed compounds were screened via molecular docking using PLANTS as virtual screening software to identify new inhibitors of Src kinase. Subsequently, all of the screened compounds were synthesized via Huisgen's 1,3-dipolar cycloaddition between terminal alkynes (1) and methyl 2-azidoacetate (2) with Cu(I) in excellent yields at room temperature. Results: In the present study, we report the design and the synthesis of a series of 1,4-disubstituted 1,2,3-triazoles involving one pot condensation of methyl 2-azidoacetate and different terminal alkynes. All the synthesized triazoles were characterized by IR, 1 H, 13 C, 19 F NMR, and HRMS. They were investigated as inhibitors of Src kinase. Conclusion: A series of 1,4-disubstituted 1,2,3-triazole compounds were synthesized through an easy, convenient Cu(I) catalyzed click reaction and evaluated for their Src kinase activity. Compound 3m exhibited significant inhibitory activity against Src Kinase. These results, along with molecular design docking observations, are significant evidence to demonstrate the compound 3m could be optimized as a potential Src kinase inhibitor in further studies.

International audience; The synthesis of the four stereoisomers of a new 1,2,3-tri-azole analogue of rhizobitoxine from serine is described. The key step is a Huisgen 1,3-dipolar cycloaddition on an ethynylglycine synthon.

International audience; Enantiomerically pure 2-, 3- or 4-pyridylalanine (pya) and 2-azatyrosine (azatyr) are known to present various biological activities. After incorporation into appropriate peptide sequences, these heterocyclic non natural a-amino acids could behave as new substrates or inhibitors of elastase from Pseudomonas aeruginosa.This enzyme is known to be involved in nosocomial infections and infections related to the cystic fibrosis disease. New efficient chemoenzymatic preparations of those compounds using a-chymotrypsin (a-CT) are presented.

International audience; α-Quaternary α-ethynyl α-amino acids are an important class of non-proteinogenic amino acids that play an important role in the development of peptides and peptidomimetics as therapeutic agents and in the inhibition of enzyme activities. This review provides an overview of the literature concerning synthesis and applications of α-quaternary α-ethynyl α-amino acids covering the period from 1977 to 2015.

International audience

Review: update on the different routes for the synthesis of the ethynylglycine synthon (R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazolidine, 56 refs.

Racemic derivatives of α-amino acid β,γ-thioenol ethers have been synthesized from homoserine through a γ-elimination on a sulfoxide derived from aspartaldehyde. Optically active derivatives were efficiently prepared from L-methionine by a Pummerer like reaction.

Strategies for the synthesis of optically active aspartaldehyde derivatives are reviewed. Most of them are using the chiral pool: allylglycine or naturally occurring homoserine, aspartic acid or methionine and side chain modifications. This will be developed in the first part. Some other original routes are also displayed in the second part. Different aspects of each strategy are discussed: the nature and number of steps, the problem of protecting groups, the price and availability of starting materials. Some synthetic applications of such interesting chiral synthons are shown in the last part.

First results in the synthesis of chiral non racemic ethynylglycine derivatives from protected L-serinal are described.

International audience; Glutamate ((S)-Glu)is the major excitatory amino acid in the central nervous system. It acts by stimulating ionotropic and metabotropic glutamate receptors (iGluR and mGluR respectively). Glutamate has been shown to be involved not only in many neuropathologies such as anxiety, pain, ischemia, Parkinson's disease, epilepsy and schizophrenia. More recently, mGlu receptors have also been detected in non-neuronal cells suggesting that they could be implicated in carcinogenesis. mGlu receptors are G-protein-coupled receptors and eight subtypes (mGluR1 to 8) have been identified and classified into three groups (I-III) based upon sequence homology, transduction mechanism and pharmacological profile. Because of their modulating properties, mGlu receptors are recognized as promising therapeutic targets and many ligands (agonists and antagonists) have been prepared to better understand the pharmacology of mGlu receptors in order to selectively activate the different groups and subtypes of receptors. An -amino acid moiety can be found in all mGlu receptors competitive ligands and most of the side chains hold an acidic function. Examination of the glutamate binding site in the mGlu receptors and pharmacological data of some ligands shows that sterically constrained structures with an optimal distance between functional groups could lead to potent and selective new ligands. It is known that introducing an unsaturation in a biologically active structure could modify the conformation of the molecule and thus the biological activity. In this respect, the synthesis of new acetylenic analogues of glutamate will be described.

A C 2 symmetrical chiral ligand derived from (R,R)-trans-1,2-diaminocyclohexane is highly effective in the symmetric cis-dihydroxylation of aromatic and aliphatic di- and trisubstituted olefins under stoichiometric conditions