Design, synthesis and biological evaluation of glycolamide, glycinamide, and ß-amino carbonyl 1,2,4-triazole derivatives as DPP-4 inhibitors.

Through modification of the skeleton of Sitagliptin and Vildagliptin, we successfully synthesized and built-up four series of 1,2,4-triazole derivatives, containing N,O-disubstituted glycolamide, N,N'-disubstituted glycinamide, ß-amino ester, and ß-amino amide as linkers, for the development of new dipeptidyl peptidase 4 (DPP-4) inhibitors. The synthetic strategy for glycolamides or glycinamides involved convenient two-steps reaction: functionalized transformation of 2-chloro-N-(2,4,5-triflurophenyl)acetamide 9 (hydroxylation or amination) and esterification or amidation of 1,2,4-triazole-3-carboxylic acid. On the other hand, the one-pot synthesis procedure, including substitution and deprotection, was developed for the preparation of ß-amino carbonyl 1,2,4-triazoles from (1H-1,2,4-triazol-3-yl)methanol 12 or (1H-1,2,4-triazol-3-yl)methanamine 13 and Boc-(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid 14. All of glycolamides, glycinamides, and ß-amino carbonyl 1,2,4-triazoles were also evaluated against DPP-4 inhibitory activity. Based on the SAR study of DPP-4 inhibitory capacity, ß-amino ester 5n and ß-amino amide 1,2,4-triazoles 6d and 6p possessed the significant inhibition of DPP-4 (IC50 < 51.0 nM), particularly for compound 6d (IC50 = 34.4 nM). The selectivity evaluation indicated compound 5n and 6p had excellent selectivity over QPP, DPP-8, and DPP-9. In addition, the docking results revealed compounds 5n and 6p provided stronger π-π stacking interaction with residue Phe357 than 1,5-disubstituted 1,2,4-triazole 6d and Sitagliptin 1. In summary, compounds 5n and 6p could be promising lead compounds for further development of DPP-4 inhibitor.

Design, Synthesis, and Activity Study of Water-Soluble, Rapid-Release Propofol Prodrugs.

In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma while preserving its safety. In animal experiments, prodrugs (3e, 3g, and 3j) were significantly better than fospropofol (the only water-soluble propofol prodrug that has been used clinically) in terms of safety, onset, and duration time of anesthesia. Their molar dose, onset time, and anesthesia duration time were comparable to those of propofol, helping to maintain the clinical benefits of propofol. The experimental results showed the potential of such compounds as water-soluble prodrugs of propofol.

Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.

Human thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing enzyme which plays a crucial role in regulating numerous redox signalling pathways within the cell. While its functioning is important in all cells, levels of TrxR1 expression are higher in cancer cells, possibly as an adaptation to much higher levels of reactive oxygen species and the need for more extensive DNA synthesis. This makes TrxR1 an attractive target for cancer therapy development. Inspired by the structure of disulphide compounds which have advanced through various stages of clinical development, we designed a series of dithiodiglycolic acid derivatives. These were prepared from respective thiol synthons using an iodine- or benzotriazolyl chloride-promoted oxidative disulphide bond formation. Inhibition of TrxR present in cell lysates from human neuroblastoma cells (SH-SY5Y) and rat liver cells indicated several compounds with a potential for TrxR inhibition. Some of these compounds were also tested for growth inhibition against two human cancer cell lines and normal human keratinocytes.

Synthesis of Complex Glycolates by Enantioconvergent Addition Reactions.

The unique role that stereochemistry plays in molecular recognition events continues to provide a driving force for synthesizing organic compounds in enantioenriched form. The tendency of enantioenriched organic compounds to revert to an entropically favored racemic state in the presence of viable racemization pathways (e.g., the enolization of stereogenic carbonyl derivatives) can sometimes interfere with this objective; however, beginning with Noyori's foundational disclosure of a dynamic kinetic transfer hydrogenation, the ability to channel racemic, configurationally labile starting materials through stereoconvergent reaction pathways has been recognized as a powerful strategy in asymmetric synthesis. Proton transfer, retro-aldol, retro-Michael, reversible redox events, and other processes that can be deleterious to asymmetric synthesis are exploitable in enantioconvergent reactions using chiral small molecules and enzymes as asymmetric catalysts. Enantioselective reduction of configurationally labile carbonyl derivatives bearing a C-H acidic chiral center are particularly common. Because facile racemization is vital to stereocontrol in these transformations, hydrogenations of ß-dicarbonyls are commonplace, while less activated substrates have been used less commonly. Our entry into enantioconvergent catalysis evolved from a long-standing interest in the synthesis of complex glycolates and began with the development of a general Noyori-type transfer hydrogenation of α-keto esters. Key innovations in this work include the identification of a new terphenylsulfonamide-Ru(II) complex, which displays unusual preference toward reduction of α-keto esters, and the observation that α-keto esters racemize under mildly basic conditions. This work was extended to the dynamic kinetic hydrogenation of racemic acyl phosphonates. Moreover, the recent recognition that the mechanistic paradigm underlying enantioconvergent hydrogenation chemistry can be extended to diverse carbon-centered nucleophiles has led to advances in the art. Our lab has developed a number of enantioconvergent tertiary alcohol syntheses. In the context of carbon-centered nucleophiles, we have focused on the use of α-keto esters; however, in the latter part of this Account, we will briefly describe our nascent efforts to develop dynamic kinetic additions of carbon-centered nucleophiles to ß-oxo acid derivatives. While the enantioconvergent hydrogenation of ß-keto acid derivatives is carried out on 100-ton scale annually, non-hydrogenative transformations of these compounds constitute an underexplored subclass of enantioconvergent reactions. With regard to future prospects, a trend toward transformations that afford increasing levels of molecular complexity is apparent. It can be expected that the burgeoning field of asymmetric 1,2-addition chemistry will further drive this chemistry to encompass a wider array of enantioconvergent additions. Additionally, the continued exploration of these chemistries in the context of less conventional electrophiles, as well as identifying novel or overlooked modes of racemization, holds considerable potential.

Synthesis of Complex Tertiary Glycolates by Enantioconvergent Arylation of Stereochemically Labile α-Keto Esters.

Enantioconvergent arylation reactions of boronic acids and racemic ß-stereogenic α-keto esters have been developed. The reactions are catalyzed by a chiral (diene)Rh(I) complex and provide a wide array of ß-stereogenic tertiary aryl glycolate derivatives with high levels of diastereo- and enantioselectivity. Racemization studies employing a series of sterically differentiated tertiary amines suggest that the steric nature of the amine base additive exerts a significant influence on the rate of substrate racemization.

Synthetic investigation, physicochemical characterization and antibacterial evaluation of ternary Bi(III) systems with hydroxycarboxylic acid and aromatic chelator substrates.

Due to its physical and chemical properties, bismuth (Bi(III)) is widely used in the treatment of several gastrointestinal and skin diseases, and infections caused by bacteria. Herein, its known antimicrobial potential was taken into consideration in the synthesis of two new hybrid ternary materials of Bi(III) with the physiological α-hydroxycarboxylic glycolic acid and 1,10-phenanthroline (phen), [Bi2(C2H2O3)2(C2H3O3)(NO3)]n. nH2O (1) and [Bi(C12H8N2)(NO3)4](C10H8N4) (2), aiming at improving its antibacterial properties. Their physicochemical characterization was carried out through elemental analysis, FT-IR, atomic absorption spectroscopy, single crystal X-ray diffraction, thermogravimetric analysis (TGA), photoluminescence, and 13C MAS-NMR techniques. The antimicrobial activity of the title complexes was directly linked to Bi(III) coordination environment and the incipient aqueous chemistry. For their antibacterial assessment, minimum inhibitory concentration (MIC), zone of inhibition (ZOI), and bacteriostatic-bacteriocidal activity were determined in various Gram positive (Staphylococcus aureus, Bacillus subtilis and Bacillus cereus) and Gram negative (Escherichia coli and Xanthomonas campestris) bacterial cultures, in reference to a positive control (ampicillin), encompassing further comparisons with literature data. The findings reveal that the new hybrid bismuth materials have significant antimicrobial effects against the employed bacteria. Specifically, 2 exhibits better antimicrobial properties than free Bi(NO3)3 and phen. On the other hand, 1 is bacteriostatic toward four microorganisms except X. campestris, with 2 being bacteriocidal toward four microorganisms except B. cereus. Collectively, the new hybrid, well-defined, and two of the rarely crystallographically characterized Bi(III) materials a) exhibit properties reflecting their physicochemical nature and reactivity, and b) are expected to contribute to the development of efficient metallodrugs against drug-resistant bacterial infections.

Conversion of Undaria pinnatifida residue to glycolic acid with recyclable methylamine in low temperature hydrothermal liquefaction.

The conversion of Undaria pinnatifida residue to glycolic acid was carried out using methylamine as catalyst by hydrothermal method at relatively low temperature. GC-MS and HPLC were used to identify the composition of bio-oil and liquid products which provide the knowledge of the chemical reaction pathways of the hydrothermal liquefaction. The main liquid product was organic acid which contained glycolic acid, lactic acid, formic acid and acetic acid. And the major organic acid was glycolic acid with the highest yield of 46.52% or 33.98% of dry biomass. Methylamine promoted the dissolution of cellulose from Undaria pinnatifida residue, and significantly improved the yield of glycolic acid. The mechanism of HTL was investigated and the results show that the carbocation C3 was attacked by methylamine molecule which led to the high yield of glycolic acid. In addition, the recovery of methylamine was studied and the highest recovery rate reached 99.28%.

Mutagenesis Analysis Reveals Distinct Amino Acids of the Human Serotonin 5-HT2C Receptor Underlying the Pharmacology of Distinct Ligands.

While exploring the structure-activity relationship of 4-phenyl-2-dimethylaminotetralins (PATs) at serotonin 5-HT2C receptors, we discovered that relatively minor modification of PAT chemistry impacts function at 5-HT2C receptors. In HEK293 cells expressing human 5-HT2C-INI receptors, for example, (-)-trans-3'-Br-PAT and (-)-trans-3'-Cl-PAT are agonists regarding Gαq-inositol phosphate signaling, whereas (-)-trans-3'-CF3-PAT is an inverse agonist. To investigate the ligand-receptor interactions that govern this change in function, we performed site-directed mutagenesis of 14 amino acids of the 5-HT2C receptor based on molecular modeling and reported G protein-coupled receptor crystal structures, followed by molecular pharmacology studies. We found that S3.36, T3.37, and F5.47 in the orthosteric binding pocket are critical for affinity (Ki) of all PATs tested, we also found that F6.44, M6.47, C7.45, and S7.46 are primarily involved in regulating EC/IC50 functional potencies of PATs. We discovered that when residue S5.43, N6.55, or both are mutated to alanine, (-)-trans-3'-CF3-PAT switches from inverse agonist to agonist function, and when N6.55 is mutated to leucine, (-)-trans-3'-Br-PAT switches from agonist to inverse agonist function. Notably, most point-mutations that affected PAT pharmacology did not significantly alter affinity (KD) of the antagonist radioligand [3H]mesulergine, but every mutation tested negatively impacted serotonin binding. Also, amino acid mutations differentially affected the pharmacology of other commercially available 5-HT2C ligands tested. Collectively, the data show that functional outcomes shared by different ligands are mediated by different amino acids and that some 5-HT2C receptor residues important for pharmacology of one ligand are not necessarily important for another ligand.

Structure-Activity Studies of Bis-O-Arylglycolamides: Inhibitors of the Integrated Stress Response.

The integrated stress response comprises multiple signaling pathways for detecting and responding to cellular stress that converge at a single event-the phosphorylation of Ser51 on the α-subunit of eukaryotic translation initiation factor 2 (eIF2α). Phosphorylation of eIF2α (eIF2α-P) results in attenuation of global protein synthesis via the inhibitory effects of eIF2α-P on eIF2B, the guanine exchange factor (GEF) for eIF2. Herein we describe structure-activity relationship (SAR) studies of bis-O-arylglycolamides, first-in-class integrated stress response inhibitors (ISRIB). ISRIB analogues make cells insensitive to the effects of eIF2α-P by activating the GEF activity of eIF2B and allowing global protein synthesis to proceed with residual unphosphorylated eIF2α. The SAR studies described herein support the proposed pharmacology of ISRIB analogues as binding across a symmetrical protein-protein interface formed between protein subunits of the dimeric eIF2B heteropentamer.

Selective catalysis for cellulose conversion to lactic acid and other α-hydroxy acids.

This review discusses topical chemical routes and their catalysis for the conversion of cellulose, hexoses, and smaller carbohydrates to lactic acid and other useful α-hydroxy acids. Lactic acid is a top chemical opportunity from carbohydrate biomass as it not only features tremendous potential as a chemical platform molecule; it is also a common building block for commercially employed green solvents and near-commodity bio-plastics. Its current scale fermentative synthesis is sufficient, but it could be considered a bottleneck for a million ton scale breakthrough. Alternative chemical routes are therefore investigated using multifunctional, often heterogeneous, catalysis. Rather than summarizing yields and conditions, this review attempts to guide the reader through the complex reaction networks encountered when synthetic lactates from carbohydrate biomass are targeted. Detailed inspection of the cascade of reactions emphasizes the need for a selective retro-aldol activity in the catalyst. Recently unveiled catalytic routes towards other promising α-hydroxy acids such as glycolic acid, and vinyl and furyl glycolic acids are highlighted as well.

Novel organic salts based on fluoroquinolone drugs: synthesis, bioavailability and toxicological profiles.

In order to overcome the problems associated with low water solubility, and consequently low bioavailability of active pharmaceutical ingredients (APIs), novel organic salts containing fluoroquinolones (e.g. ciprofloxacin and norfloxacin) were prepared, using an optimized synthetic procedure based on direct protonation, with different biocompatible counter ions such as mesylate, gluconate and glycolate. All the prepared organic salts were characterized by spectroscopic techniques, mass spectrometry and thermal analysis. Solubility studies in water and simulated biological fluids at 25°C and 37°C were also performed. Additionally, octanol-water and phospholipid-water partition coefficients were measured at 25°C. The cytotoxicity and anti-inflammatory efficacy using an human cell model of intestinal epithelia (Caco-2 cells) were also evaluated and compared to those of the parent APIs. The adequate selection of the biocompatible anions allows the tuning of important physical, thermal and toxicological properties.

Large-scale preparation of (13) C-labeled 2-(phenylthio)acetic acid and the corresponding labeled sulfoxides and sulfones.

We have developed large-scale efficient procedures for the conversion of commercially available [(13) C]- or [(2) H3 ,(13) C]methanol and (13) CO2 or (13) C-labeled bromoacetic acid to 2-(phenylthio)[1,2-(13) C2 ]-, [1-(13) C]-, and [2-(13) C]acetic acid. The resulting derivatives are versatile, chemically stable, and nonvolatile two-carbon labeling precursors. We have used the (13) C-isotopomers of 2-(phenylthio)acetic acid in the synthesis of (13) C-labeled acrylic acid, methacrylic acid, and trans-crotonic acid.

Synthesis and quantitative analysis of diastereomeric linked ester conjugates with remote stereocenters using high-field NMR and chiral HPLC.

A stereochemically safe high-yielding procedure for linking unprotected as well as protected hydroxycarboxylic acids to chiral secondary alcohols via glycolic acid linker is proposed. L-menthol has been linked with both enantiomers of mandelic, malic, and methoxyphenylacetic acid using bromo- or iodoacetyl group as a precursor of the glycolic acid linker. High-field nuclear magnetic resonance (NMR) and chiral high-performance liquid chromatography (HPLC) determination of high diastereomeric ratio (dr) (>99%) of the products bearing remote stereocenters was explored. Chiral HPLC allowed quantitation of the diastereomers up to dr 99.9/0.1. High-field NMR quantitation of the diastereomeric and parent alcoholic impurities in esters was demonstrated at the molar 0.3% and 0.03% levels, respectively. These analyses were done via comparison of integral intensities from major component (13)C satellites in (1)H or even in (13)C spectra to the (1)H or (13C signals of impurities. Despite lower sensitivity, the last option generally has much better selectivity. In this way the dynamic resolution is brought down by two orders.

Extraction behavior and selective separation of lead(II) using N,N-dioctyldiglycol amic acid.

Selective separation of lead ions (Pb(2+)) from aqueous solutions containing multiple divalent metal ions (Pb(2+), Cu(2+), Cd(2+), Zn(2+), Mn(2+), Co(2+), and Ni(2+)) was investigated using liquid-liquid extraction. N,N-Dioctyldiglycol amic acid (DODGAA) enabled quantitative extraction and efficient separation of Pb(2+) from the metal ion mixture under mildly acidic conditions. Compared with conventional commercial extractants, DODGAA provided better extraction and excellent selectivity for Pb(2+). The extraction of Pb(2+) with DODGAA proceeded through a proton-exchange reaction and formed a 1:2 complex, Pb(DODGAA)(2). The Pb(2+) was readily stripped from the extracting phase under acidic conditions, and the organic solution with DODGAA could be recycled.

Role of alkyl chain branching on aggregation behavior of two symmetrical diglycolamides: small angle neutron scattering studies.

The two long alkyl chain derivatives of diglycolamide (DGA), viz. N,N,N',N'-tetraoctyl diglycolamide (TODGA) and N,N,N',N'-tetra(2-ethylhexyl)-diglycolamide (T2EHDGA) have been found promising for actinide partitioning from high-level waste. The solvent extraction studies have suggested the participation of three to four DGA molecules in the extracted complex of trivalent actinides and lanthanides. However, coordination of 3-4 tridentate DGA ligands with trivalent f-elements seems to be unusual due to restricted coordination sites in these metal ions. Nonetheless, the extraction data have been explained in view of the formation of aggregates of these ligands in the organic phase. Small Angle Neutron Scattering (SANS) measurements were carried out to investigate the aggregation behavior of DGA ligands in deuterated n-dodecane. The aggregation of DGA molecules was facilitated by the presence of acid. However, the presence of nitrate ions in the aqueous phase had no significant effect on the aggregation of DGA. Similarly, the presence of metal ions such as Sr(II) or Eu(III) marginally affected the aggregation tendency of DGA molecules. TODGA displayed higher aggregation tendency than that of T2EHDGA. The extraction data of trivalent f-elements were in conformity with the aggregation tendency of the two DGA ligands.

Synthesis, molecular docking and antiamnesic activity of selected 2- naphthyloxy derivatives.

The present paper describes the design and synthesis of a series of some 2-naphthyloxy derivatives with their antiamnesic activity using mice as the animal model and piracetam as the reference drug. All the synthesized compounds were characterized by spectroscopic techniques and were screened for their efficacy as cognition enhancers by elevated plus maze test and acetylcholinestrase inhibitory assay. Molecular modeling and docking studies of the selected compounds into the crystal structure of acetylcholinestrase complexed with functional ligand succinylcholine using GRAMM software was performed in order to predict the affinity and orientation of the synthesized derivatives at the active site. The binding energy of ligands was calculated using ArgusLab software. The docking score and hydrogen bonds formed with surrounding amino acids show the good agreement with predicted binding affinities obtained by molecular docking studies, as verified by acetylcholinestrase activity.

Asymmetric synthesis of diverse glycolic acid scaffolds via dynamic kinetic resolution of α-keto esters.

The dynamic kinetic resolution of α-keto esters via asymmetric transfer hydrogenation has been developed as a technique for the highly stereoselective construction of structurally diverse ß-substituted-α-hydroxy carboxylic acid derivatives. Through the development of a privileged m-terphenylsulfonamide for (arene)RuCl(monosulfonamide) complexes with a high affinity for selective α-keto ester reduction, excellent levels of chemo-, diastereo-, and enantiocontrol can be realized in the reduction of ß-aryl- and ß-chloro-α-keto esters.

Synthesis of gamma,delta-unsaturated glycolic acids via sequenced brook and Ireland--claisen rearrangements.

Organozinc, -magnesium, and -lithium nucleophiles initiate a Brook/Ireland-Claisen rearrangement sequence of allylic silyl glyoxylates resulting in the formation of gamma,delta-unsaturated alpha-silyloxy acids.

Synthesizing and binding dual-mode poly (lactic-co-glycolic acid) (PLGA) nanobubbles for cancer targeting and imaging.

Accurate assessment of tumor boundaries and recognition of occult disease are important oncologic principles in cancer surgeries. However, existing imaging modalities are not optimized for intraoperative cancer imaging applications. We developed a nanobubble (NB) contrast agent for cancer targeting and dual-mode imaging using optical and ultrasound (US) modalities. The contrast agent was fabricated by encapsulating the Texas Red dye in poly (lactic-co-glycolic acid) (PLGA) NBs and conjugating NBs with cancer-targeting ligands. Both one-step and three-step cancer-targeting strategies were tested on the LS174T human colon cancer cell line. For the one-step process, NBs were conjugated with the humanized HuCC49 Delta C(H)2 antibody to target the over-expressed TAG-72 antigen. For the three-step process, cancer cells were targeted by successive application of the biotinylated HuCC49 Delta C(H)2 antibody, streptavidin, and the biotinylated NBs. Both one-step and three-step processes successfully targeted the cancer cells with high binding affinity. NB-assisted dual-mode imaging was demonstrated on a gelatin phantom that embedded multiple tumor simulators at different NB concentrations. Simultaneous fluorescence and US images were acquired for these tumor simulators and linear correlations were observed between the fluorescence/US intensities and the NB concentrations. Our research demonstrated the technical feasibility of using the dual-mode NB contrast agent for cancer targeting and simultaneous fluorescence/US imaging.

Oxidation of glycerol to glycolate by using supported gold and palladium nanoparticles.

Glycolic acid is an important chemical that has uses as a cleaning agent as well as a chemical intermediate. At present glycolic acid is manufactured from either chloroacetic acid or from formaldehyde hydrocyanation, both routes being nongreen and using nonsustainable resources. We investigate the possibility of producing glycolate from the oxidation of glycerol, a sustainable raw material. We show that by using 1 % wt Au/carbon catalysts prepared using a sol-immobilization method glycolate yields of ca. 60 % can be achieved, using hydrogen peroxide as oxidant in an autoclave reactor. We describe and discuss the reaction mechanism and consider the reaction conditions that maximize the formation of glycolate.