Design, Synthesis, and Activity Evaluation of Stereoconfigured Tartarate Derivatives as Potential Anti-inflammatory Agents In Vitro and In Vivo.

Preclinical and clinical data reveal that inflammation is strongly correlated with the pathogenesis of a number of diseases including those of cancer, Alzheimer, and diabetes. The inflammatory cascade involves a multitude of cytokines ending ultimately with the activation of COX-2/LOX for the production of prostaglandins and leukotrienes. While the available inhibitors for these enzymes suffer from nonoptimal selectivity, in particular for COX-2, we present here the results of purposely designed tartarate derivatives that exhibit favorable selectivity and significant effectiveness against COX-2 and LOX. Integrated approaches of molecular simulation, organic synthesis, and biochemical/physical experiments identified 15 inhibiting COX-2 and LOX with respective IC50 4 and 7 nM. At a dose of 5 mg kg-1 to Swiss albino mice, 15 reversed algesia by 65% and inflammation by 33% in 2-3 h. We find good agreement between experiments and simulations and use the simulations to rationalize our observations.

Synthesis of Natural (-)-Antrocin and its Enantiomer via Stereoselective Aldol Reaction.

The total synthesis of (-)-antrocin and its enantiomer are presented. Antrocin (-)-1 is an important natural product which acts as an antiproliferative agent in a metastatic breast cancer cell line (IC50: 0.6 µM). The key features of this synthesis are: (a) selective anti-addition of trimethylsilyl cyanide (TMSCN) to α,ß-unsaturated ketone; (b) resolution of (±)-7 using chiral auxiliary L-dimethyl tartrate through formation of cyclic ketal diastereomers followed by simple column chromatography separation and acid hydrolysis; (c) substrate-controlled stereoselective aldol condensation of (+)-12 with monomeric formaldehyde and pyridinium chlorochromate (PCC) oxidation for synthesis of essential lactone core in (-)-14; and (d) non-basic Lombardo olefination of the carbonyl at the final step to yield (-)-antrocin. In addition, (+)-9 cyclic ketal diastereomer was converted to (+)-antrocin with similar reaction sequences.

Lipid Based Aqueous Core Nanocapsules (ACNs) for Encapsulating Hydrophillic Vinorelbine Bitartrate: Preparation, Optimization, Characterization and In vitro Safety Assessment for Intravenous Administration.

BACKGROUND: Vinorelbine bitartrate (VRL) is an antimitotic agent approved by FDA for breast cancer and non-small cell lung cancer (NSCLC) in many countries. However, high aqueous solubility and thermo degradable nature of VRL limited the availability of marketed dosage forms. OBJECTIVES: The current work is focused on the development of lipid based aqueous core nanocapsules which can encapsulate the hydrophilic VRL in the aqueous core of nanocapsules protected with a lipidic shell which will further provide a sustained release. METHODS: The ACNs were prepared by double emulsification technique followed by solvent evaporation. Box Behnken Design was utilized to optimize the formulation and process variables. Thirteen batches were generated utilizing lipid concentration, surfactant concentration and homogenizer speed as dependent variables (at three levels) and particle size and encapsulation efficiency as critical quality attributes. The ACNs were characterized for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, morphology by Transmission Electron Microscopy (TEM) and in vitro release. The ACNs were further evaluated for safety against intravenous administration by haemocompatibility studies. RESULTS: Results demonstrated that lipidic nanocapsules enhanced the entrapment efficiency of VRL up to 78%. Transmission Electron Microscopy revealed spherical shape of ACNs with core-shell structure. The GMS-VRL-ACNs showed that release followed Korsemeyer peppas kinetics suggesting Fickian diffusion. Moreover, the compliance towards haemocompatibility studies depicted the safety of prepared nanocapsules against intravenous administration. CONCLUSION: ACNs were found to be promising in encapsulating high aqueous soluble anticancer drugs with enhanced entrapment and safety towards intravenous administration.

Decarboxylative alkenylation.

Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.

Solving manufacturing problems for L-carnitine-L-tartrate to improve the likelihood of successful product scale-up.

L-carnitine-L-tartrate, a non-essential amino acid, is hygroscopic. This causes a problem in tablet production due to pronounced adhesion of tablets to punches. A 33 full factorial design was adopted to suggest a tablet formulation. Three adsorbents were suggested (Aerosil 200, Aerosil R972, talc) to reduce stickiness at three concentrations (1, 3 and 5 %), and three fillers (mannitol, Avicel PH 101, Dibasic calcium phosphate) were chosen to prepare 27 formulations. Micromeritic properties of formulations were studied, and tablets were prepared by wet granulation. Absence of picking, sticking or capping, recording of sufficient hardness, acceptable friability and tablet ejection force indicated formulation success. The resulting formulation prepared using Avicel PH 101 and 1 % Aerosil 200 was submitted to further investigation in order to choose the most suitable compression conditions using a 33 full factorial design. Variables included compression force, tableting rate and magnesium stearate (lubricant) concentration. The formulation prepared at compression force of 25 kN, using 2 % magnesium stearate, at a production rate of 30 tablets/ minute, was found to be the most appropriate scale up candidate.

Chemometrics Tools in Detection and Quantitation of the Main Impurities Present in Aspirin/Dipyridamole Extended-Release Capsules.

Aspirin (ASP) and dipyridamole (DIP) in combination is widely used in the prevention of secondary events after stroke and transient ischemic attack. Salicylic acid is a well-known impurity of ASP, and the DIP extended-release formulation may contain ester impurities originating from the reaction with tartaric acid. UV spectral data analysis of the active ingredients in the presence of their main impurities is presented using multivariate approaches. Four chemometric-assisted spectrophotometric methods, namely, partial least-squares, concentration residuals augmented classical least-squares (CRACLS), multivariate curve resolution (MCR) alternating least-squares (ALS), and artificial neural networks, were developed and validated. The quantitative analyses of all the proposed calibrations were compared by percentage recoveries, root mean square error of prediction, and standard error of prediction. In addition, r(2) values between the pure and estimated spectral profiles were used to evaluate the qualitative analysis of CRACLS and MCR-ALS. The lowest error was obtained by the CRACLS model, whereas the best correlation was achieved using MCR-ALS. The four multivariate calibration methods could successfully be applied for the extended-release formulation analysis. The application results were also validated by analysis of the stored dosage-form solution, which showed a susceptibility of DIP esterification in the extended-release formulation. Statistical comparison between the proposed and official methods showed no significant difference.

Production of tartrates by cyanide-mediated dimerization of glyoxylate: a potential abiotic pathway to the citric acid cycle.

An abiotic formation of meso- and DL-tartrates in 80% yield via the cyanide-catalyzed dimerization of glyoxylate under alkaline conditions is demonstrated. A detailed mechanism for this conversion is proposed, supported by NMR evidence and (13)C-labeled reactions. Simple dehydration of tartrates to oxaloacetate and an ensuing decarboxylation to form pyruvate are known processes that provide a ready feedstock for entry into the citric acid cycle. While glyoxylate and high hydroxide concentration are atypical in the prebiotic literature, there is evidence for natural, abiotic availability of each. It is proposed that this availability, coupled with the remarkable efficiency of tartrate production from glyoxylate, merits consideration of an alternative prebiotic pathway for providing constituents of the citric acid cycle.

Nanoscale amphiphilic macromolecules with variable lipophilicity and stereochemistry modulate inhibition of oxidized low-density lipoprotein uptake.

Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) and counteract foam cell formation, a key characteristic of early atherogenesis. To investigate the influence of lipophilicity and stereochemistry on the AMs' physicochemical and biological properties, mucic acid-based AMs bearing four aliphatic chains (2a) and tartaric acid-based AMs bearing two (2b and 2l) and four aliphatic chains (2g and 2k) were synthesized and evaluated. Solution aggregation studies suggested that both the number of hydrophobic arms and the length of the hydrophobic domain impact AM micelle sizes, whereas stereochemistry impacts micelle stability. 2l, the meso analogue of 2b, elicited the highest reported oxLDL uptake inhibition values (89%), highlighting the crucial effect of stereochemistry on biological properties. This study suggests that stereochemistry plays a critical role in modulating oxLDL uptake and must be considered when designing biomaterials for potential cardiovascular therapies.

Synthesis of tartaric acid analogues of FR258900 and their evaluation as glycogen phosphorylase inhibitors.

Di-O-cinnamoylated, -p-coumaroylated, and -feruloylated d-, l- and meso-tartaric acids were synthesized as analogues of the natural product FR258900, a glycogen phosphorylase (GP) inhibitor with in vivo antihyperglycaemic activity. The new compounds inhibited rabbit muscle GP in the low micromolar range, and bound to the allosteric site of the enzyme. The best inhibitor was 2,3-di-O-feruloyl meso-tartaric acid and had Ki values of 2.0µM against AMP (competitive) and 3.36µM against glucose-1-phosphate (non-competitive).

A novel green template assisted synthesis of hydroxyapatite nanorods and their spectral characterization.

Hydroxyapatite [HAP, Ca10(PO4)6(OH)2] is the main inorganic component of bone material and is widely used in various biomedical applications due to its excellent bioactivity and biocompatibility. In this paper we have reported the synthesis of hydroxyapatite nanorods by green template method using the extracts of three different natural sources which contain tartaric acid and also from commercially available one. The extracts of banana, grape and tamarind are taken as the sources of tartaric acid. The as-synthesized samples were characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDAX). Also the antibacterial activity of HAP with different concentrations against two pathogen bacteria strains Escherichia coli (E. coli) and Klebsiella (Gram-negative bacteria) were tested. The results show that the particles of all the samples are of nanosized and pure. The crystallinity decreases as changing the sources of tartaric acid from commercial to natural one and also changing the natural sources from banana to tamarind extracts. The formation of nanorods are found in all the samples but the nanorods with uniform size distribution can be obtained only by using the tamarind extract as the source of tartaric acid. Moreover, the as-synthesised HAP nanorods derived from natural sources exhibited a strong antibacterial activity against both E. coli and Klebsiella at a concentration of 100 µl. The HAP nanorods synthesized by this method can act as a potential candidate for various biomedical applications.

In situ synthesis of twelve dialkyltartrate-boric acid complexes and two polyols-boric acid complexes and their applications as chiral ion-pair selectors in nonaqueous capillary electrophoresis.

In this paper, twelve dialkyltartrate-boric acid complexes and two polyols-boric acid complexes were in situ synthesized by the reaction of different dialkyltartrates or polyols with boric acid in methanol containing triethylamine. All of the twelve dialkyltartrate-boric acid complexes were found to have relatively good chiral separation performance in nonaqueous capillary electrophoresis (NACE). Their chiral recognition effects in terms of both enantioselectivity (α) and resolution (R(s)) were similar when the number of carbon atoms was below six in the alkyl group of alcohol moiety. The dialkyltartrates containing alkyl groups of different structures but the same number of carbon atoms, i.e. one of straight chain and one of branched chain, also provided similar chiral recognition effects. Furthermore, it was demonstrated for the first time that two methanol insoluble polyols, D-mannitol and D-sorbitol, could react with boric acid to prepare chiral ion-pair selectors using methanol as the solvent medium.

Design, synthesis, and application of tartaric acid derived N-spiro quaternary ammonium salts as chiral phase-transfer catalysts.

A novel class of tartaric acid-derived N-spiro quaternary ammonium salts was synthesised starting from known TADDOLs. These compounds were found to catalyse the asymmetric α-alkylation of glycine Schiff bases with high enantioselectivities and in good yields.

Effects of hydrophobic chain length on temperature dependence of monolayer behavior of ester-type tartaric geminis.

Ester-type tartaric gemini amphiphiles bearing two carboxyl groups and two hydrophobic alkanoyl groups were prepared from L-tartaric acid, and the pressure-area (π-A) isotherms for a series of symmetric tartaric gemini amphiphiles were measured by the conventional film-balance technique. The effects of the length of the hydrophobic alkanoyl chains and of the subphase temperature (T(sub)) on the π-A isotherms for these compounds were examined. As the length of the hydrophobic alkyl chain increased, a more tightly packed monolayer was formed at the air-water interface. The melting temperature (T(m)) of the monolayer on the water surface was evaluated from the subphase temperature (T(sub)) dependence of the monolayer static elasticity ε(s), based on a π-A isotherm. A clear relationship between T(m) and hydrophobic carbon number (n) was observed for 2D monolayers of tartaric geminis on water surfaces, as well as for fatty acids and/or 3D solids.

ESI-MS investigation of solvent effects on the chiral recognition capacity of tartar emetic towards neutral side-chain amino acids.

The effect of solvent systems on previously-reported ESI-MS based proton-assisted enantioselective molecular recognition phenomena of tartar emetic, L-antimony(III)-tartrate, was evaluated. This was achieved by carrying out a series of competitive binding experiments using chiral selectors, bis(sodium) D- and -L-antimony(III)-tartrates with chiral selectands, neutral side-chain amino acid enantiomeric isotopomers of alanine (Ala), valine (Val), leucine (Leu) and phenylalanine (Phe), in three different solvent systems, ACN/H(2)O (75/25 v/v), H(2)O (100%) and H(2)O/MeOH (25/75 v/v). Observations from these experiments suggest that the effect of solvent systems on previously reported proton-assisted chiral recognition capacity of D,L-antimony(III)-tartrates is small, but not negligible. It was observed that an ACN/H(2)O (75/25 v/v) solvent system facilitates and enhances the chiral discrimination capacity of protonated {[D,L-Sb(2)-tar(2)][H]}(-) ionic species. Further, amino acid enantiomers showed a general trend of increasing selectivity order, Val ≤ Ala < Leu ≈ Phe towards the protonated {[D,L-Sb(2)-tar(2)][H]}(-) ionic species which was independent of the solvent system employed. The lack of enantioselective binding for {[D,L-Sb(2)-tar(2)]}(2-) ionic species was consistently recorded in respective mass spectra from all performed experiments, which suggests that ESI-friendly solvent systems have no effect and do not influence this phenomenon.

Total regioselective control of tartaric acid.

An efficient strategy to synthesize tartaric acid building blocks for totally regioselective transformations or derivatizations was disclosed. Starting from l-tartaric acid or l-dimethyl tartrate, respectively, we obtained type I and II building blocks with orthogonal sets of protecing groups (4-8 steps, 38-56% overall yield).

Diastereoselective hydrophosphonylation of imines using (R,R)-TADDOL phosphite. Asymmetric synthesis of alpha-aminophosphonic acid derivatives.

Efficient synthesis of alpha-aminophosphonic acid derivatives is achieved, the key step being a diastereoselective hydrophosphonylation of N-diphenylphosphinyl imines using a readily available chiral cyclic (R,R)-TADDOL-phosphite derived from inexpensive natural tartaric acid.

Structure and activity relationships of tartrate-based TACE inhibitors.

The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.

Synthesis and characterization of long-chain tartaric acid diamides as novel ceramide-like compounds.

Ceramides play a crucial role in the barrier function of the skin as well as in transmembrane signaling. In this study long aliphatic chain tartaric acid diamides able to replace ceramides in an in vitro model of the stratum corneum lipid matrix due to their similar physico-chemical properties were synthesized from diacetoxysuccinic anhydride in four steps. Their pro-apoptotic effect on fibroblast cells was also investigated.

Synthesis of acetal protected building blocks using flow chemistry with flow I.R. analysis: preparation of butane-2,3-diacetal tartrates.

The syntheses of butane-2,3-diacetal protected tartrate derivatives are described using continuous flow processing techniques with in-line purification and I.R. analytical protocols.

In situ synthesis of di-n-butyl l-tartrate-boric acid complex chiral selector and its application in chiral microemulsion electrokinetic chromatography.

A novel procedure for in situ assembling a complex chiral selector, di-n-butyl l-tartrate-boric acid complex, by the reaction of di-n-butyl l-tartrate with boric acid in a running buffer was reported and its application in the enantioseparation of beta-blockers and structural related compounds by chiral microemulsion electrokinetic chromatography (MEEKC) has been demonstrated. In order to achieve a good enantioseparation, the effect of dibutyl l-tartrate and sodium tetraborate concentration, surfactant identity and concentration, cosurfactant, buffer pH and composition, organic modifiers, as well as applied voltage and capillary length were investigated. Ten pairs of enantiomers that could not be separated with only dibutyl l-tartrate, obtained good chiral separation using the complex chiral selector; among them, seven pairs could be baseline resolved under optimized experimental conditions. The fixation of chiral centers by the formation of five-membered rings, and being oppositely charged with basic analytes were thought to be the key factors giving the complex chiral selector a superior chiral recognition capability. The effect of the molecular structure of analytes on enantioseparation was discussed in terms of molecular interaction.