M-anisic Acid Research Articles

Investigating the Metabolic Mechanisms of Butaselen, An Ebselen Analog.

Butaselen is an ebselen analog that is under clinical trials for treating hepatic and pulmonary fibrosis. Our previous studies showed that butaselen is mainly present in human plasma in the form of M2, a free Se-methylated metabolite. This study aimed to investigate the metabolic mechanisms of butaselen. Butaselen was incubated with human plasma. Butaselen immediately disappeared, and the butaselen-HSA (human serum albumin) adduct was detected by HPLC-HRMS, showing that butaselen covalently binds to HSA. The butaselen-HSA adduct was precipitated using acetonitrile and then incubated with PBS, Cys, and GSH for 1 hour. The product was M1, a reduced form of butaselen. The results indicated that HSA, Cys, and GSH can reduce the butaselen-HSA covalent bond. The binding site for butaselen could be the cysteine-34 residue of HSA through pronase and trypsin hydrolysis. Incubating butaselen with cysteine, butaselen-Cys, butaselen-2Cys, and M1 were generated, indicating the covalent binding and reduction of butaselen by cysteine. We incubated liver microsomes and cytosol with butaselen, 6.22 and 246 nM M2 were generated, respectively. The results demonstrated that cytosolic enzymes are mainly involved in M2 production. The amount of M2 in the liver cytosol decreased from 246 nM to 2.21 nM when 10 mM m-anisic acid (a specific TPMT enzyme inhibitor) was added, showing that TPMT is responsible for M2 formation. Butaselen was covalently bound to HSA, and the binding site was the cysteine-34 residue of HSA. The butaselen-HSA adduct was reduced by free thiol compounds to generate M1. M1 was further metabolized to M2 by cytosolic TPMT. This study provides a basis for studying the pharmacokinetics of selenium-containing drugs.

Rapid Enantioselective and Diastereoconvergent Hybrid Organic/Biocatalytic Entry into the Oseltamivir Core.

A formal synthesis of the antiviral drug (-)-oseltamivir (Tamiflu) has been accomplished starting from m-anisic acid via a dissolving metal or electrochemical Birch reduction. The correct absolute stereochemistry is efficiently set through enzyme-catalyzed carbonyl reduction on the resultant racemic α,β-unsaturated ketone. A screen of a broad ketoreductase (KRED) library identified several that deliver the desired allylic alcohol with nearly perfect facial selectivity at the new center for each antipodal substrate, indicating that the enzyme also is able to completely override inherent diastereomeric bias in the substrate. Conversion is complete, with d-glucose serving as the terminal hydride donor (glucose dehydrogenase). For each resulting diastereomeric secondary alcohol, O/N-interconversion is then efficiently effected either by synfacial [3,3]-sigmatropic allylic imidate rearrangement or by direct, stereoinverting N-Mitsunobu chemistry. Both stereochemical outcomes have been confirmed crystallographically. The α,β-unsaturation is then introduced via an α-phenylselenylation/oxidation/pyrolysis sequence to yield the targeted (S)-N-acyl-protected 5-amino-1,3-cyclohexadiene carboxylates, key advanced intermediates for oseltamivir pioneered by Corey (N-Boc) and Trost (N-phthalamido), respectively.

Promising photocatalytic degradation of lignin over carbon quantum dots decorated TiO2 nanocomposite in aqueous condition

The complex branched structure of lignin offers challenges in its chemical/biological transformation. The recalcitrant nature hampers its effective utilization towards the synthesis of potential chemicals and products through depolymerization. Herein, we demonstrate the effective process for lignin decomposition via photocatalysis using CQDs decorated TiO2 nanohybrid in aqueous conditions. Indeed, the sophisticated analytical determinations, including powder XRD, HR-TEM, and XPS, witnessed the structural characteristics of the as-prepared TiO2/CQDs nanocomposite. The photocatalyst promoted a nearly complete decomposition of commercial alkali lignin up to 99 % with the direct sunlight illumination, yielding a different variety of market-value lignin derivative products like m-anisic acid (3-methoxybenzoic acid) and p-hydroxybenzoic acid (PHBA) with 20 % and 16.25 % selectivity, respectively, through the probable oxidation mechanism. Upon verifying its effectiveness towards the decomposition of kraft lignin, it showed a promising response (80 % conversion) within 6 h of photocatalysis. The recyclability study showed that the photocatalyst has an exceptional photostability.

Conformational Landscape of m-Anisic Acid and Its Complexes with Formic Acid.

Four conformers of m-anisic acid were observed in a supersonic expansion using Fourier transform microwave spectroscopy. These conformers correspond to different relative orientations of the acid and methoxy groups and have their planar skeletons stabilized by resonance. When formic acid was present in the jet, the spectra of four m-anisic acid-formic acid heterodimer conformers were detected. The complexes are formed from the interaction of formic acid with each of the four observed conformers of m-anisic acid through the typical acid-acid sequential cycle with a double O-H···O═C hydrogen bond interaction in a pseudo eight-membered ring arrangement. The four heterodimer forms retain the same four m-anisic acid conformational geometries and the same relative abundances of the m-anisic acid monomeric forms in the supersonic expansion. This proves that a kinetic mechanism dominates the formation of complexes in the jet.

Depolymerization of Laccase-Oxidized Lignin in Aqueous Alkaline Solution at 37 °C

Lignin depolymerization is a coveted process for the generation of high-value compounds from a low-cost feedstock. This report describes a chemoenzymatic approach for the depolymerization of lignin involving a laccase-catalyzed oxidation under ambient air at room temperature followed by a base (NaOH)-induced depolymerization in aqueous solution at 37 °C. Two-dimensional nuclear magnetic resonance heteronuclear single quantum coherence spectroscopy, gel permeation chromatography, and liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-Q-TOF-MS) analysis indicated the degradation of lignin and the formation of water-soluble fractions containing guaiacol, syringol, vanillic acid, m-anisic acid, and veratric acid. Furthermore, guaiacol and veratric acid are the main final products in the chemoenzymatic decomposition of a β-O-4 model compound.

Treatment of 3,3′-dimethoxybenzidine in sludge by advance oxidation process: Degradation products and toxicity evaluation

Studies on the oxidation products of organic pollutants and their toxicity in textile dyeing sludge after the sludge was treated by the advance oxidation processes were limited, since textile dyeing sludge was a complicated mixture. For the first time, simulated sludge was used to study the degradation mechanism of 3,3′-dimethoxybenzidine (DMB) during the combined ultrasound-Mn(VII) treatment. The toxicity of DMB and its products was also evaluated. The results indicated that the compositions and microstructures of polyaluminium chloride (PAC)- and polyferric sulphate (PFS)-based simulated sludge were similar to those of real textile dyeing sludge. The optimum conditions of ultrasound-Mn(VII) treatment were: a KMnO4 dosage of 40 μM, an ultrasound power density of 0.36 W cm−3, and a reaction time of 20 min. 98.24% of DMB and 63.04% of total organic carbon (TOC) in the simulated sludge were removed. Six products, that is, 2-nitroanisole, 3-methoxy-4-nitrophenol, vanillylmandelic acid, vanillyl alcohol, m-anisic acid, and benzoic acid, were identified by GC-MS and LC-MS-MS. It was noted that all of these identified products were also detected in the real textile dyeing sludge after the ultrasound-Mn(VII) treatment. All of them were less toxic than DMB. Moreover, 53.30% and 54.80% of toxicity toward the alga Desmodesmus subspicatus and the bacterium Vibrio fischeri were removed in simulated sludge, respectively. Therefore, simulated sludge was helpful for studying a pollutant's degradation mechanism in the complex sludge mixtures. The results would also provide some useful suggestions for the sludge disposal after the sludge was treated by the advance oxidation processes.

Structural evidence of polymorphism and conformational isomorphism of a somewhat flexible molecule: m-anisic acid

m-Anisic acid is generally recognized as a safe (GRAS) flavouring substance. Its GRAS status and the functional groups present in the molecule make it an interesting candidate for pharmaceutical co-crystallization studies. The knowledge of m-anisic acid crystalline structure/polymorphic behaviour is important information for its applications. In this work, a crystalline structure of m-anisic acid form I, T fus = 105 °C, was solved by X-ray diffraction: monoclinic, space group P21/n, with a = 13.8075(5) A, b = 5.0221(2) A, c = 21.4455(8) A, β = 99.325(3)°, Mr = 331.37, V = 1467.44(10) A3, Z = 8 and R = 0.0395 (CCDC No. 985352). A recent paper by Raffo et al. (J Mol Struct 1070:86–93, 2014) (CCDC No. 985637) also resolved the structure, and within experimental error, the two structures are equal. The molecular flexibility of m-anisic acid results in the presence of two conformers in the unit cell, a rare case of conformational isomorphism. These two conformers were found by ab initio calculations to differ in energy by 4.9 kJ mol−1. Solid samples were generated by crystallization from solutions and by melt cooling. Using a multidisciplinary approach involving thermal analysis (DSC, PLTM), infrared spectroscopy and X-ray powder diffraction, a new monotropic solid form II, T fus = 94 °C, was identified and characterized. Polymorph II slowly transforms into polymorph I at room temperature.

Total synthesis of the aromatase inhibitor dihydroisocoumarin via protective opening of lactones

Asymmetric total synthesis of a dihydroisocoumarin, (3R,4R)-(−)-6-methoxy-1-oxo-3-pentyl-3,4-dihydro-1H-isochromen-4-yl acetate (1) starting from commercially available m-anisic acid is described. Herein, we depict the use of protective opening of lactones and construction of δ lactone. The synthesis involves Wittig, Grubbs cross metathesis, and Sharpless dihydroxylation reactions.

First General, Direct, and Regioselective Synthesis of Substituted Methoxybenzoic Acids by Ortho Metalation

New general methodology of value in aromatic chemistry based on ortho-metalation sites in o-, m-, and p-anisic acids (1-3) (Scheme 1) is described. The metalation can be selectively directed to either of the ortho positions by varying the base, metalation temperature, and exposure times. Metalation of o-anisic acid (1) with s-BuLi/TMEDA in THF at -78 degrees C occurs exclusively in the position adjacente to the carboxylate. On the other hand, a reversal of regioselectivity is observed with n-BuLi/t-BuOK. With LTMP at 0 degrees C, the two directors of m-anisic acid (2) function in concert to direct introduction of the metal between them while n-BuLi/t-BuOK removes preferentially the proton located ortho to the methoxy and para to the carboxylate (H-4). s-BuLi/TMEDA reacts with p-anisic acid (3) exclusively in the vicinity of the carboxylate. According to these methodologies, routes to very simple methoxybenzoic acids with a variety of functionalities that are not easily accessible by other means have been developed (Table 1).

Stimulation of intrachromosomal homologous recombination in mammalian cells by ain inhibitor of poly(ADP-ribosylation)

We determined the effect of 3-methoxybenzamide (3-MB), a competitive inhibitor of poly(ADP-ribose) polymerase (E.C. 2.4.2.30), on intrachromosomal homologous recombination in mouse Ltk- cells. We used a cell line that contained in its genome two defective Herpes thymidine kinase (tk) genes as closely linked direct repeats. Intrachromosomal homologous recombination events were monitored by selecting for tk-positive segregants that arose during propagation of the cells and recombination rates were determined by fluctuation analysis. We found that growth of cells in the continuous presence of 2mM 3-MB increased intrachromosomal recombination between 3 and 4-fold. Growth of cells in the presence of 2mM m-anisic acid, a non-inhibitory analog of 3-MB, had no effect on intrachromosomal recombination rates. Additionally, we found that 3-MB increased both gene conversions and crossovers to similar extents, adding to the evidence that these two types of intrachromosomal rearrangements share a common pathway. These findings contrast with our previous studies [Waldman, B.C. and Waldman, A.S. (1990) Nucleic Acids Res., 18, 5981-5988] in which we determined that 3-MB inhibits illegitimate recombination and has no effect on extrachromosomal homologous recombination in mouse Ltk- cells. An hypothesis is offered that explains the influence of 3-MB on different recombination pathways in mammalian cells in terms of the role that poly(ADP-ribosylation) plays in DNA break-repair.

Control of the Birch Reduction ofm-Anisic Acid to Produce Specific 3-Oxocyclohexenecarboxylic Acids

An efficient method is reported of synthesizing relatively large quantities of methyl 3-oxo-1-cyclohexenecarboxylate (2b), a useful dienophile and photoreagent, from m-anisic acid (3) through the Birch reduction. Treating 3 with lithium in liquid ammonia produces any one of the four specific 3-oxocyclohexene carboxylic acids depending on the conditions selected.

A sensitive liquid chromatographic assay for plasma aspirin and salicylate concentrations after low doses of aspirin.

An original, highly sensitive and specific high performance liquid chromatographic method has been developed for the measurement of aspirin and salicylate in plasma. Minimum concentrations of 10 micrograms/L (aspirin) and 0.5 mg/L (salicylate) can be measured using 1 ml of plasma. After collection, plasma is first treated with physostigmine sulfate to inhibit enzymatic hydrolysis of aspirin to salicylate. Maximal recovery is achieved using an acid extraction into anhydrous diethyl ether with a subsequent drying-down step in an iced water bath. Aspirin and salicylate are separated by elution with a mixture of methanol, 1-butanol, orthophosphoric acid, and water on a reversed-phase octadecyl silane column at 47 degrees C and detected at 234 nm by ultraviolet absorption. Quantitation is achieved using the peak height ratio of aspirin and salicylate to internal standard (m-anisic acid). The assay has been used for the study of simultaneous aspirin and salicylate pharmacokinetics after a single oral dose of 100 mg soluble glycinated aspirin for platelet antiaggregatory therapy in six subjects, one of whom was also studied after receiving a 600 mg dose.