Thioester Compounds Research Articles

S-Arylation of Thioic S-Acid Using Thianthrenium Salts via Photoactivation of Electron Donor-Acceptor Complex.

Thioesters make up an important class of bioactive compounds. Due to their chemoselectivity, they have been widely used in the synthesis of a wide range of complex bioactive molecules and natural products. At present, chemists have developed a variety of methods for the preparation of thioester compounds. However, these methods usually require the use of transition metal catalysis or harsh reaction conditions. The strategy of synthesizing thioester compounds via visible light-induced electron donor-acceptor (EDA) complex reactions avoids the problems associated with conventional methods through the development of photocatalysis. Here we report a sustainable method for thiocarbonylating aryl sulfonium salts via a visible light-induced EDA complex process without transition metals.

Visible Light-Accelerated Palladium-Catalyzed Thiocarbonylation Using Oxalic Acid Monothioester with Aryl/Alkenyl Sulfonium Salts.

Herein, we present a decarboxylative thiocarbonylation of aryl and alkenyl sulfonium salts with oxalic acid monothioethers (OAMs), which can be achieved by visible light-accelerated palladium catalysis. Sulfonium salts are widely available, and OAM is an easily accessible and stored reagent; this mild reaction method can also be used for the synthesis of different types of thioester compounds. The reaction represents a new application of visible light-accelerated palladium catalysis in catalytic decarboxylative cross-couplings.

Spectroscopic and structural studies on phenyl and pentafluorophenyl trifluorothioacetate, and pentafluorophenyl trifluoroacetate, CF3C(O)SC6H5, CF3C(O)SC6F5 and CF3C(O)OC6F5.

Phenyl and pentafluorophenyl trifluorothioacetate, CF3C(O)SC6H5 and CF3C(O)SC6F5, were prepared by condensation of CF3C(O)Cl and the corresponding mercaptan RSH under vacuum conditions. The compounds were isolated and properly characterized by using infrared spectroscopy, UV-Vis, multinuclear NMR spectroscopy techniques and by mass spectrometry. The crystal structures have been determined for both CF3C(O)SC6H5 and according to the best of our knowledge the not yet reported in the literature CF3C(O)SC6F5 species. The conformational preferences of the three title species were also determined by means of FTIR spectroscopy. In the case of CF3C(O)OC6F5, the FTIR spectrum was also measured in an Ar-matrix and a subsequent photochemical study was performed. The main stable photoproduct found, beside CO, was the ether C6F5OCF3. Quantum-chemical calculations were used to determine the conformational preferences and complement the experimental structure parameters as well as to interpret the UV-Vis spectra determined for the three species under study. As a result of all these experimental determinations complemented with computational calculations, it can be affirmed that the title compounds present a single syn conformation in the analyzed phases (syn with respect to the CO double bond and the opposite C-chalcogen single bond). This finding reconfirms the syn conformational transferability found so far for both thioesters and esters, a result that is closely related to the properties of these families in biological processes.

An Efficient Synthesis of Thioesters Starting from N‐Arylthiocarbamates and Indoles: A Newman‐Kwart‐Type Rearrangement

AbstractAn efficient method for synthesizing thioester compounds under metal‐free conditions was reported. Thus, a series of indole‐substituted thioesters were easily obtained in the presence of PhICl2 (dichloroiodo‐benzene) starting from N‐arylthiocarbamates and indoles. This Newman‐Kwart‐type rearrangement reaction features metal free, base free, mild reaction conditions, good functional tolerance, and good yield, showing potential value for preparing some biologically and pharmaceutically active compounds.

Simultaneous Quantification of Biothiols and Deciphering Diverse GSH Stability in Different Live Cells by 19F-Tag.

GSH, Cys, Hcy, and H2S are important biothiols and play important roles in the living systems. Quantitative and simultaneous determination of these biothiols under physiological conditions is still a challenge. Herein, we developed an effective 19F-reactive tag that readily interacts with these four biothiols for the generation of stable thioether products that have distinguishable 19F-chemical shifts. These thioester compounds encode the characteristic fingerprint profiles of each biothiols, allowing one to simultaneously quantify and determine these biothiols by 1D 19F NMR spectroscopy. The intra-/extracellular GSH in live cells was assessed by the established strategy, and remarkable variations in the GSH stability were determined between the normal mammalian cells and cancer cells. It is notable that GSH hydrolyzes efficiently in the out-membrane of the cancer cells and the lysates. In contrast, GSH remains stable in the tested normal cells.

Synthesis, Characterization, and Antibacterial Activity of Ni(II), Pd(II), and Pt(II) Complexes with 2-benzoylthiobenzimidazole

The thioester compound of 2-benzoylthiobenzimidazole was prepared by S-acylation of 2-mercaptobenzimidazole with benzoyl chloride and reactions of divalent Ni, Pd, and Pt salts with one equivalent of thioester compound a new complexes were isolated in a high percentage. A tetradentate thioester compound and a bivalent metal complexes were identified by CHNS analysis, IR, magnetic susceptibility, molar conductivity, UV-Vis, and 1H, 13C NMR spectroscopies. The anti-bacterial activity of the thioester compound and the bivalent metal complexes were studied using disk diffusion test method against the bacterial species, Staphylococcus aureus, and Pseudomonas aeruginosa. The divalent metal complexes demonstrated a greater activities compared to thioester compound a lone. Structural analysis showed that 2-benzoylthiobenzimidazole L behaves as a neutral four coordination modes compound and bonds to the bivalent metals cation through two nitrogen, sulfur and oxygen atoms. Our study informed the formation of four-coordinate square planar complexes structure around divalent metal salts of Ni, Pd, and Pt.

Identification of auto-inhibitors in the reused culture media of the Chlorophyta Scenedesmus acuminatus

Auto-inhibition is widely observed in the microalgal media reuse, but auto-inhibitors in the reused culture media are not well understood. In the current study, microalgal media reuse experiments, target-directed organic matter separation and identification via gas chromatography-mass spectrometry (GC–MS) were conducted to elucidate the growth inhibitors in the reused media of the Chlorophyta Scenedesmus acuminatus. Results indicated growth inhibitors in the reused media belonged to small molecule dissolved organic matter that was mainly produced at the declining growth phase. Using an ultraviolet detector-guided resin separation procedure, dissolved organic matter in the reused media was partitioned into 13 fractions. Growth inhibition tests showed that inhibitors were in the fraction 8. GC–MS analysis revealed that fraction 8 contained fatty acid, phenol, alicyclic, and thioester compounds along with hexadecanoic acid and octadecanoic acid as its major components. Further experiments verified the existence of hexadecanoic acid and octadecanoic acid in the original reused media, and commercial standards also confirmed the growth inhibition to S. acuminatus by hexadecanoic acid and octadecanoic acid. This is the first study to confirm that microalgae can produce hexadecanoic acid and octadecanoic acid which inhibit their own growth. This study establishes an innovative target-directed method to fractionate, screen and identify compounds in dissolved organic matter. Meanwhile, the results of this study could be conducive to develop effective ways to reuse microalgal culture media and save water in microalgal cultivation.

Mesogenic materials incorporating 4H-1,2,4-triazol-3-thiol moiety: Synthesis, characterization and liquid crystals study

Three series of monomers, polymers and thioester cyclic compounds containing 4H-1,2,4-triazol-3-thiol moiety were synthesized and examined for their liquid crystalline properties. All monomers, polymers and thioester compounds were characterized by elemental analysis and FTIR, 1H-NMR and mass spectroscopy. The phase transition and mesomorphic properties were investigated by polarized optical microscope (POM) and differential scanning calorimetry (DSC). The monomer with terminal phenyl substituent display dimorphism nematic and smectic A (SmA) mesophases. The corresponding polymers derived from acrylic and phenyl acrylic acid monomers show nematic mesophase. The only thioester cyclic compound derived from terephtaloyl chloride show nematic mesophase. The liquid crystalline behavior has been discussed in terms of structural property relationships.

The Structural Alteration and Aggregation of Bovine Lens Gamma-Crystallin by Homocysteinylation; The Pathomechanism Underlying Cataract Development During Hyperhomocysteinimia.

A significant association between increased level of blood homocysteine (hyperhomocysteinimia) and various eye pathological disorders including cataract has been reported. This metabolic byproduct is converted into a highly reactive cyclic thioester compound, homocysteine thiolactone (HCTL), which can potentially react with free amino groups in protein. In the current study, as bovine lens γ-Crystallin (γ-Cry) was incubated with HCTL, various spectroscopic techniques, gel mobility shift assay, and microscopic analysis were applied to characterize structural variation and aggregation of this protein. According to the fluorescence results, HCTL-induced structural alteration was accompanied with the significant enhancement in surface hydrophobicity of γ-Cry. Also, this cyclic thioester was indicated to alter γ-Cry secondary structures and to induce aggregation of this protein. The results of gel mobility shift assay suggest the involvement of disulfide bond cross-linking in formation of the protein aggregates. In conjunction with Thioflavin T and Congo red assays, the microscopic analysis also suggests that HCTL can induce formation of ordered aggregate entities in bovine lens γ-Cry. The relationship between γ-Cry insolubilization/aggregation and growth of cataract disorders has been already reported. Therefore, the induction of structural alteration and aggregation of γ-Cry by HCTL can elucidate the pathomechanism underlying cataract disorders particularly in hyperhomocysteinimia.

High-Resolution Metabolomics with Acyl-CoA Profiling Reveals Widespread Remodeling in Response to Diet*

The availability of acyl-Coenzyme A (acyl-CoA) thioester compounds affects numerous cellular functions including autophagy, lipid oxidation and synthesis, and post-translational modifications. Consequently, the acyl-CoA level changes tend to be associated with other metabolic alterations that regulate these critical cellular functions. Despite their biological importance, this class of metabolites remains difficult to detect and quantify using current analytical methods. Here we show a universal method for metabolomics that allows for the detection of an expansive set of acyl-CoA compounds and hundreds of other cellular metabolites. We apply this method to profile the dynamics of acyl-CoA compounds and corresponding alterations in metabolism across the metabolic network in response to high fat feeding in mice. We identified targeted metabolites (>50) and untargeted features (>1000) with significant changes (FDR < 0.05) in response to diet. A substantial extent of this metabolic remodeling exhibited correlated changes in acyl-CoA metabolism with acyl-carnitine metabolism and other features of the metabolic network that together can lead to the discovery of biomarkers of acyl-CoA metabolism. These findings show a robust acyl-CoA profiling method and identify coordinated changes of acyl-CoA metabolism in response to nutritional stress.

Excited state dynamics of Photoactive Yellow Protein chromophores elucidated by high-resolution spectroscopy and ab initio calculations

We report on experimental high-resolution spectroscopic studies in combination with advanced theoretical calculations that focus on the excited-state dynamics of various forms of the chromophore of the Photoactive Yellow Protein (PYP), and the dependence of these dynamics on conformational and isosteric structure, as well as the biological environment. Three-colour nanosecond multiphoton ionization pump-probe studies confirm and extend previous conclusions that the dominant decay channel of the lowest excited pipi* state (the so-called V' state) of methyl-4-hydroxycinnamate is picosecond internal conversion to the adiabatically lower nPi* state, and enable us to resolve apparent contradictions with picosecond pump-probe studies. Comparison of multiphoton ionization and laser induced fluorescence excitation spectra leads to the assignment of the hitherto elusive excitation spectrum of the V(pipi*) state. Complexation of methyl-4-hydroxycinnamate with water radically changes the excited-state dynamics; internal conversion to the npi* state is absent, and bond isomerization channels instead play a prominent role. Excited states of the thio-ester compound, the form in which the chromophore is present in PYP, have till the present study remained out of reach of gas-phase studies. The excitation spectra obtained here show a broad, almost structureless band system, giving evidence for enhanced nonradiative decay channels. The gas-phase results will be discussed in the context of results from ultrafast studies on these two chromophores in solution.

Unusual physical properties in B phase of polar bent-core thioester compound

Bent-core compound, 4-chloro-1,3-phenylene bis{4-[(n-undecyloxybenzoyl)-sulfanyl]benzoate}, has been studied by dielectric spectroscopy, DSC calorimetry, and electro-optic methods. As found, the spontaneous polarization of the B phase is by one order of magnitude smaller than for B 2 phases of nOSOR series studied by us before. Its temperature dependence is characteristic for B 1 phase, observed for shorter homologues of nOSORs. Measurements of the complex electric permittivity were carried out in the frequency range from 40 to 15 MHz using gold-coated electrodes. Electro-optic studies have been done applying AWAT HG 1.9 µm cells with strongly rubbed polymer layers. Such cells facilitate inhomogeneous planar alignment, which under strong electric field transforms into a mono-domain exhibiting switching behavior. Dielectric and electro-optic data of bent-core compounds will be discussed taking into account molecular structure and phase structure as well.

Resting state connectivity in posterior cingulate and hyppocampus in mild Alzheimer's disease and mild cognitive impairment

butyrylcholinesterase specific imaging agents. Methods: A series of benzoate oxyand thioesters were synthesized containing the N-methylpiperidinyl moiety. The benzoate oxyesters were measured for hydrolysis using changes in UV absorption for the benzoate reactants and products and comparable thioesters were analyzed using the Ellman method. In addition, thioesters of several acetyl-, propionyland butyryl-containing oxyester cholinesterase imaging agents were synthesized and their kinetic parameters evaluated using the Ellman method. Several of the thioester compounds were used for histochemical staining of post-mortem human tissue to assess their distribution and specificity towards acetylcholinesterase or butyrylcholinesterase. Results:Nmethylpiperidinyl oxyand thioesters (Figure 1) were synthesized in analogous reaction procedures. Enzyme kinetic analyses indicated comparable interactions of oxyand thioesters with acetylcholinesterase and butyrylcholinesterase. Histochemical studies indicate a unique distribution of each thioester, dependent upon their specificity towards the cholinesterases. Conclusions: We have established a strategy for the development of cholinesterase ligands based on thioesters of N-methyl piperidinol. Molecules derived from this moiety can be rapidly evaluated in vitro for their potential as imaging agents. Imaging agents developed using this approach have the potential to detect cholinesterase levels associated with disease pathology, thus providing an approach for early diagnosis and treatment monitoring of AD. P4-066 RESTING STATE CONNECTIVITY IN POSTERIOR CINGULATE AND HYPPOCAMPUS IN MILD ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT Patrizia Montella, Fabrizio Esposito, Manuela de Stefano, Daniela Buonanno, Angiola Maria Fasanaro, Mario Cirillo, Antonella Paccone, Gioacchino Tedeschi, Second University of Naples, Naples, Italy; University of Naples Federico II, Naples, Italy; Second University of Naples, Naples, Italy; Second University of Naples, Naples, Italy; Neurological Institute for Diagnosis and Care “Hermitage Capodimonte”, Naples, Italy.

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

Recent iPrEx clinical trial results provided evidence that systemic preexposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) can partially prevent rectal HIV transmission in humans. Similarly, we have previously demonstrated that systemic administration of the same FTC-TDF combination efficiently prevented rectal transmission in humanized bone marrow/liver/thymus (BLT) mice. The CAPRISA 004 trial recently demonstrated that topical application of the tenofovir could partially prevent vaginal HIV-1 transmission in humans. To further validate the usefulness of the BLT mouse model for testing HIV prevention strategies, we evaluated the topical administration of tenofovir as used in CAPRISA 004 to prevent vaginal HIV transmission in BLT mice. Our results demonstrate that vaginally administered 1% tenofovir significantly reduced HIV transmission in BLT mice (P = 0.002). Together with the results obtained after systemic antiretroviral PrEP, these topical inhibitor data serve to validate the use of humanized BLT mice to evaluate both systemic and topical inhibitors of HIV transmission. Based on these observations, we tested six additional microbicide candidates for their ability to prevent vaginal HIV transmission: a C-peptide fusion inhibitor (C52L), a membrane-disrupting amphipathic peptide inhibitor (C5A), a trimeric d-peptide fusion inhibitor (PIE12-Trimer), a combination of reverse transcriptase inhibitors (FTC-TDF), a thioester zinc finger inhibitor (TC247), and a small-molecule Rac inhibitor (NSC23766). No protection was seen with the Rac inhibitor NSC23766. The thioester compound TC247 offered partial protection. Significant protection was afforded by FTC-TDF, and complete protection was offered by three different peptide inhibitors tested. Our results demonstrate that these effective topical inhibitors have excellent potential to prevent vaginal HIV transmission in humans.

Molecular and Electronic Structure of δ-Valerothiolactone

The crystal structure of the six-member heterocyclic δ-valerothiolactone (1-thiocycloalkan-2-one) compound has been determined by X-ray diffraction at low temperature, revealing that its skeleton adopts a half-chair conformation. The conformation around the thioester group is almost planar with an anti orientation of the C=O double bond with respect the S-C single bond [C(2)-S(1)-C(6)-O(1) = 176.26(8)°]. The skeletal parameters, especially valence angles [∠C5-C6-S = 121.19(6)°, ∠O=C6-C5 = 122.25(8)°, ∠C6-S-C2 = 106.80(4)°], differ from those typically found in acyclic thioester compounds, symptomatic of the presence of strain effects. The conventional ring strain energy was determined to be 7.5 kcal/mol at the MP2/6-311++G(d,p) level of calculation within the hyperhomodesmotic model approximation. Moreover, the valence electronic structure was investigated by HeI photoelectron spectroscopy assisted by quantum chemical calculations at the OVGF/6-311++G(d,p) level of theory. The first three bands at 9.35, 9.50, and 11.53 eV denote ionizations related with the n(S), n(O), and π(C=O) orbitals, respectively, demonstrating the importance of the -SC(O)- group in the outermost electronic properties.

Room Temperature Ferroelectric Mixture of Chiral and Achiral Thioesters

Dielectric properties of the mixture of two thioester compounds: 4-8-alkoxybenzoate-thiocarboxyl S-4-pentylphenyl (8OS5), (s)-4-(1-methylheptyloxy)biphenyl-4-thiocarboksyl 4-9-alkilphenyl (MHOBS9) are presented. The chiral compound exhibits nematic (N ⁄ ) and ferroelectric smectic C ⁄ phase (SmC ⁄ ). The achiral compound shows N, SmA and monotropic SmC and SmB phases. the mixture of both compounds of 0.5 molar fraction shows SmC ⁄ in the wider temperature range than pure MHOBS9. The mixture was studied using frequency domain dielectric spectroscopy. Dielectric measurements for the SmC ⁄ phase of the mixture revealed Goldstone mode at higher frequencies and Maxwell‐Wagner relaxation at low frequencies.

Evolutionary divergence and functions of the human acyl-CoA thioesterase gene (ACOT) family

The acyl-CoA thioesterase gene (ACOT) family encodes enzymes that catalyse the hydrolysis of acyl-CoA thioester compounds, also known as activated fatty acids, to their corresponding non-esterified (free) fatty acid and coenzyme A (CoASH). These enzymes play a very important role in lipid metabolism by maintaining cellular levels and proper ratios of free and activated fatty acids, as well as CoASH. Within the acyl-CoA family there are two distinct subgroups, type I and type II. Despite catalysing the same reaction, the two groups are not structurally similar and do not share sequence homology, strongly suggesting convergent evolution. This suggestion is further supported if one compares the human with the mouse and rat ACOT gene families. To date, four human type I ACOTs have been identified which belong to the α/β-hydrolase fold enzyme superfamily. Type II ACOTs fall into the 'hot dog' fold superfamily. There are currently six human type II genes; however, two homologous proteins, thioesterase superfamily members 4 (THEM4) and 5 (THEM5) share common type II structural features and, in the case of THEM4, acyl-CoA thioesterase activity -- suggesting that the family may be larger than previously realised. Although recent studies have greatly expanded the current understanding of these proteins and their physiological importance, there are a number of members whose functions are relatively unexplored and which warrant further investigation.

Matrix Photochemistry, Photoelectron Spectroscopy, Solid-Phase Structure, and Ring Strain Energy of β-Propiothiolactone

The four-membered heterocyclic beta-propiothiolactone compound was isolated in a low-temperature inert Ar matrix, and the UV-visible (200 < or = lambda < or = 800 nm) induced photochemistry was studied. On the basis of the IR spectra, the formation of methylketene (CH(3)CHCO) was identified as the main channel of photodecomposition. The formation of ethene and thiirane, with the concomitant elimination of OCS and CO, respectively, was also observed as minor decomposition channels. The valence electronic structure was investigated by HeI photoelectron spectroscopy assisted by quantum chemical calculations at the OVGF/6-311++G(d,p) level of theory. The first three bands at 9.73, 9.87, and 12.06 eV are ascribed to the n''(S), n'(O), and pi''(CO) orbitals, respectively, denoting the importance of the -SC(O)- group in the outermost electronic properties. Additionally, the structure of a single crystal, grown in situ, was determined by X-ray diffraction analysis at low temperature. The crystalline solid [monoclinic system, P21/c, a = 8.1062(1) A, b = 10.3069(2) A, c = 10.2734(1) A, beta = 107.628(1) degrees, and Z = 8] consists of planar molecules arranged in layers. The skeletal parameters, especially the valence angles [angleC2-C1-S = 94.55(7) degrees, angleOC-C = 134.20(11) degrees, angleC-S-C = 77.27(5) degrees], differ from those typically found in acyclic thioester compounds, suggesting the presence of strong strain effects. The conventional ring strain energy was determined to be 16.4 kcal/mol at the G2MP2 level of calculation within the hyperhomodesmotic model.

Specificity of action of piperidylcholine derivatives as substrates of cholinesterases of various origin

The review deals with study of enzymologic properties of a novel highly specific acetylcholinesterase substrate iodomethylate N-beta-(acetoxyethyl)piperidinium ("piperidylcholine") and its 30 derivatives that were tested as effectors of cholinesterases of mammals and various species of Pacific squids. It was proven for the first time that responsible for specificity of action was structure of cyclic ammonium grouping of the alcohol part of molecule of the ester substrate. Analysis of specificity is performed based on enzymatic analysis parameters - activity of catalytic center of cholinesterases and bimolecular constant of the reaction rate that are determined at optimal and low substrate concentrations. Among the specially synthesized group of thioester compounds there is revealed one more highly specific acetylcholine esterase substrate - N-beta-(acetoxyethyl)piperidinium.

Specificity of Acyl Transfer from 2-Mercaptobenzamide Thioesters to the HIV-1 Nucleocapsid Protein

The HIV-1 nucleocapsid protein (NCp7) is a small, highly conserved protein with two zinc-binding domains that are essential for the protein's function. Molecules that bind to and inactivate NCp7 are currently being evaluated as new antiviral drugs. In particular, derivatives based on a 2-mercaptobenzamide thioester template have been shown to specifically eject zinc from the C-terminal zinc-binding domain (ZD2) of NCp7 via acyl transfer from the thioester to a cysteine sulfur. In this study, mutational analysis of the NCp7 amino acid sequence has been used to investigate the specificity of the interaction between ZD2 and a 2-mercaptobenzamide thioester compound using UV-vis spectroscopy and mass spectrometry to monitor the rate of metal ejection from NCp7 mutant peptides and sites of acylation, respectively. We were able to extend the previously reported mechanism of action of these thioester compounds to include a secondary S to N intramolecular acyl transfer that occurs after the primary acyl transfer from the thioester to a cysteine side chain in the protein. Structural models of the thioester/ZD2 complex were then examined to identify the most likely binding orientation. We determined that position x+1 (where x is Cys36) needs to be an aromatic residue for reactivity and a hydrogen-bond donor in position x+9 is important for optimal reactivity. A basic residue (lysine or arginine) is required at position x+2 for the correct fold, while a lysine residue is needed for reactivity involving S to N acyl transfer. We report highly specific interactions between 2-mercaptobenzamide thioester compounds and NCp7 that offer a structural basis for refining and designing new antiretroviral therapeutics, directed toward a target that is resistant to viral mutation.