Dibutyric Acid Research Articles

Screening Ultra-Stable (Phenazine)dioxyalkanocic Acids with Varied Water-Solubilizing Chain Lengths for High-Capacity Aqueous Redox Flow Batteries.

Aqueous redox flow batteries (ARFBs) hold great potential for large-scale energy storage. Recently, research on aqueous flow batteries has shifted toward water-soluble organic molecules with redox capabilities to reduce the use of mineral resources. The chemical and electrochemical stabilities of organic compounds are heavily influenced by their functional groups and reaction sites. In this study, we present a low-cost synthesis of the O-alkyl-carboxylate-functionalized derivatives of 2,3-dihydroxyphenazine, namely, phenazine-(2,3-diyl) dioxy dibutyric acid (DBEP) and phenazine-(2,3-diyl)dioxy diacetic acid (DAEP), which serve as negolytes and exhibit good reversibility and high redox kinetics. The evidence is provided to clarify the capacity degradation mechanisms of DAEP and DBEP by a series of comprehensive characterizations. Similar to anthraquinones functionalized with alkyl chains, the main degradation mechanism of DAEP modified with acetic acid is due to side chain loss. Longer side chains are more stable and can withstand long-term electrochemical reactions. DBEP modified with butyric acid exhibits superior chemical and electrochemical stability. Our results demonstrate that rational molecular design and suitable membranes, such as the alkaline ARFBs based on DBEP negolyte, potassium ferrocyanide (K4Fe(CN)6) posolyte, and custom sulfonated poly(ether ether ketone) membrane, can deliver a high open-circuit voltage of 1.17 V and high capacity retention of 99.997% per cycle for over 1000 cycles at 50 mA cm-2. This study highlights the importance of not only considering the modification position of the molecules but also focusing on the influence of various side chains on the redox core's stability toward sustainable grid-scale energy storage applications.

Enabling Long-Life Aqueous Organic Redox Flow Batteries with a Highly Stable, Low Redox Potential Phenazine Anolyte.

Aqueous organic redox flow batteries (AORFBs) are considered a promising energy storage technology due to the sustainability and designability of organic active molecules. Despite this, most of AORFBs suffer from limited stability and low voltage because of the chemical instability and high redox potential of organic molecules in anolyte. Herein, we propose a new phenazine derivative, 4,4'-(phenazine-2,3-diylbis(oxy))dibutyric acid (2,3-O-DBAP), as a water-soluble and chemically stable anodic active molecules. By combining calculations and experiments, we demonstrate that 2,3-O-DBAP exhibits a higher solubility, a lower redox potential (-0.699 V vs SHE), and greater chemical stability than other O-DBAP isomers. Then, we demonstrate a long-lasting flow cell with an average discharge voltage of 1.12 V, a low fade rate of 0.0127%, and a lifespan of 62 days at pH 14 using 2,3-O-DBAP paired with ferri/ferrocyanide. The negligible self-discharge behavior also verifies the high stability of 2,3-O-DBAP. These results highlight the importance of molecular engineering for AORFBs.

Exploration of the Plausible Mechanism of Ethambutol Induced Ocular Toxicity by Using Proteomics Informed Physiologically Based Pharmacokinetic (PBPK) Modeling.

Ethambutol (EMB) is a first-line anti-tubercular drug that is known to cause optic neuropathy. The exact mechanism of its eye toxicity is unknown; however, proposition is metal chelating effect of both EMB and its metabolite 2,2'-(ethylenediamino)-dibutyric acid (EDBA). The latter is formed by sequential metabolism of EMB by alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). The purpose of this study was to predict thelevels of drug and EDBA in theeye using physiologically based pharmacokinetic (PBPK) modeling. The PBPK model of EMB was developed using GastroPlus. The intrinsic hepatic clearance of ALDH, calculated by themodel, was scaled down using proteomics data to estimate the rate of formation of EDBA in theeye. Additionally, the comparative permeability of EMB and EDBA was assessed by employing in silico and in vitro approaches. The rate of formation of EDBA in the eye and permeability data were then incorporated in a compartmental model to predict the ocular levels of EMB and EDBA. The simulation results of compartmental model highlighted that there was an on-site formation of EDBA upon metabolism of EMB. Furthermore, in silico and in vitro studies revealed that EDBA possessed much lower permeability than EMB. These observations meant that once EDBA was formed in the eye, it was not permeated out and hence achieved higher ocular concentration. The on-site formation of EDBA in the eye, its higher local concentration due to lower ocular clearance and its pre-known characteristic to chelate metal species better explains the ocular toxicity shown by EMB.

Role of cytochrome P450 genes of Trichoderma atroviride T23 on the resistance and degradation of dichlorvos

The Trichoderma has been extensively used to degrade the xenobiotics. In the present study, thirty-nine open reading frames of cytochrome P450 genes from T. atroviride T23 genome was cloned and it was found to be distributed in 29 families under 21 clades. Among them, 21 cytochrome P450 genes were involved in the degradation of xenobiotics. The quantitative expression of P450 genes in the presence of dichlorvos at 24 h showed 7 different expression patterns in the presence of 100 μg/mL, 300 μg/mL, 500 μg/mL and 1000 μg/mL of dichlorvos. The relative expression of P450 genes belongs to the family of TaCyp548, TaCyp620, TaCyp52, TaCyp528, TaCyp504 were upregulated at least 1-fold compared to the control. Significantly, the deletion of TaCyp548-2 reduced the concentration of 2,2-dichloroethanol. Further, it was observed that TaCyp548-2 belongs to the ω-hydroxylase family was responsible for fatty acid oxidation and the production of acetic acid, propionic acid, isobutyric acid and dibutyric acid to convert the 2,2-dichloroethanol to 2,2-dichloroethanolacetate. This study evidenced the involvement of Trichoderma P450 genes on dichlorvos degradation as an environmentally significant Biological control agent for the sustainable agriculture.

The addition of degradable chelating agents enhances maize phytoremediation efficiency in Cd-contaminated soils

Chelating agent-induced phytoremediation is a viable approach to completely remove heavy metals from soil. However, little attention has been paid to the interaction mechanisms between the concentration of the chelating agent and the application time on the physiological and biochemical properties of soil and plants. In this study, five chelating agents, namely ethylenediamine tetraacetic acid (EDTA), diethylenetriacetic acid (NTA), tetrasodium N, N-diacetate (GLDA), aspartate dibutyric acid ether (AES), and iminodisuccinic acid (IDSA), were used to support phytoremediation with maize and to explore the removal effect of Cd in soil. The results showed that chelating agent concentrations of 9 mmol kg−1 significantly reduced the biomass of maize. Treatment with AES at a dose of 6 mmol kg−1 significantly increased aboveground biomass, reaching a maximum of 0.92 g pot−1 in all treatments. At an AES concentration of 6 mmol kg−1, the highest shoot and root Cd levels of 7.79 and 9.86 mg kg−1, respectively, were observed, which were 3.05 and 1.60 times higher than those of the control. Total Cd extraction followed the order AES (6 mmol kg−1) > GLDA > NTA > EDTA > IDSA (3 mmol kg−1). Chelating agent treatment significantly increased the activity of antioxidant enzymes and promoted plant growth. The self-degradation of AES significantly reduced soil pH, increased soil Cd activity, and promoted Cd uptake and transportation in maize.

Global Urine Metabolomics in Patients Treated with First-Line Tuberculosis Drugs and Identification of a Novel Metabolite of Ethambutol.

Population level variation of drug metabolism phenotype (DMP) has great implications in treatment outcome, drug-related side effects, and resistance development. In this study, we used a gas chromatography-time of flight-mass spectrometry (GC-TOF-MS)-based untargeted urine metabolomics approach to understand the DMP of a tuberculosis (TB) patient cohort (n= 20) from Tripura, a state in the northeastern part of India. Urine samples collected at different postdose time points (2 h, 6 h, 12 h, 24 h, 36 h, and 48 h) from these newly diagnosed TB patients receiving first-line anti-TB drugs were analyzed, and we have successfully detected three of the four first-line drugs,viz, isoniazid (INH), ethambutol (ETB), and pyrazinamide (PZA). The majority of their known metabolites, acetyl-isoniazid (AcINH), isonicotinic acid (INA), isonicotinuric acid (INTA), 2,2'-(ethylenediimino)-dibutyric acid (EDBA), 5-hydroxypyrazinamide (5OH-PZA), pyrazinoic acid (POA), and 5-hydroxypyrazinoic acid (5OH-POA), were also detected. Analyzing the variation in abundances of drugs and their known metabolites and calculating the metabolic ratios in these samples, we offer comprehensive DMP information on this small patient cohort that represents Tripura, India. The majority (75%) of these patients are found to be slow acetylators of INH. The average metabolic ratios of POA/PZA and 5OH-POA/POA are 3.16 ± 3.03 and 6.09 ± 6.15, respectively. Employing correlation analysis of the metabolomics metadata and a manual prediction of drug catabolism, we have proposed 2-aminobutyric acid (AABA) as a novel metabolite of ETB. These observations indicate the usefulness of GC-MS-based metabolomics to characterize the DMP at a population level and also to identify novel drug metabolites.

Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy

According to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2'-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50 = 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting that in vivo pharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin).

Engineered PEI-piperazinyl nanoparticles as efficient gene delivery vectors: evidence from both in vitro and in vivo studies

A small library of polyethylenimine (PEI) nanoparticles (NPs), wherein PEI was crosslinked with piperazinyl linkers, viz., piperazine-N,N′-dibutyric acid and piperazine-N,N′-dipropanal, yielding piperazine-N,N′-dibutyramide-PEI (PBAP) and piperazine-N,N′-dipropyl-PEI (PPP) nanoparticles, was designed and synthesized. The NPs were in the size range 103–216 nm. DNA complexes of all the NPs had low toxicity and exhibited significant enhancement in transfection efficiency compared to parent PEI and commercial transfection agents. Importantly, the transfection activity of NP/DNA complexes was preserved in the presence of serum. Amongst all the formulations, the PBAP4/DNA complex exhibited the highest transfection efficiency in all the cell lines tested. Also, PBAP4 NPs efficiently protected the complexed DNA against DNase in vitro. Intravenous delivery of PBAP4/DNA complex to male Balb/c mice showed the highest gene expression in spleen cells. The results indicate that PBAP nanoparticles may be used for tissue-specific gene delivery in vivo.

New molybdenum(v) analogues of Amavadin and their redox properties

Reactions of [MoO2(acetylacetonate)2] with the proligands (N-hydroxyimino)diacetic acid (H3hidpa), R,R-2,2′-(N-hydroxyimino)dipropionic acid (R,R-H3hidpa) or R,S-2,2′-(N-hydroxyimino)dibutyric acid (R,S-H3hidba) yielded the compounds [PPh4][Δ,Λ-Mo(hida)2]·CH2Cl21, [H5O2][Δ-Mo(R,R-hidpa)2] 2, [PPh4][Mo(R,S-hidba)2]·2H2O 3a and Na[Δ,Λ-Mo(R,S-hidba)2]·¼iPr2O 3b, respectively. Reactions of H3hida with a methanolic solution of [PPh4][MoOCl4(H2O)] in the presence of NaOH (ca. pH 8) provided an alternative synthesis for 1. The complex of 1 when transferred into CH2Cl2 using [PPh4]Br yielded brown block-like crystals from a CH2Cl2–EtOH solution, however, 2 and 3b were crystallised from H2O and MeCN solutions with [H5O2]+ and [Na]+ counter cations, respectively. X-Ray crystallography confirmed the same distinctive eight-co-ordinate geometry of the complex anions of 1, 2 and 3b as identified for Amavadin, the form in which vanadium(IV) is bound in Amanita muscaria mushrooms. EPR and UV/vis spectra recorded for 1, 2 and 3a are consistent with the presence of molybdenum(V). Cyclic voltammetric studies using a glassy carbon working electrode in CH2Cl2 for 1 exhibited a reversible MoVI/MoV and a quasi-reversible MoV/MoIV redox couple at E1/2 = +0.96 and −0.99 V (vs. a saturated calomel electrode), respectively. Complex 3a also displayed a reversible MoVI/MoV redox couple at E1/2 = +0.77 V, whereas the MoV/MoIV couple was irreversible (Epc = −1.28 V). Additional electrochemical studies with 2 recorded a reversible MoVI/MoV redox couple in Me2SO (E1/2 = +0.77 V), however in H2O this one-electron oxidation process is irreversible.

Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells.

Zinc-chelating agents, including ethambutol and its metabolite 2,2'(ethylenediamino)-dibutyric acid (EDBA) are toxic to retinal ganglion cells through a glutamate dependent mechanism. We explored whether such cell death was mediated through the caspase family of cysteine proteases. Retinal cultures were treated with EDBA alone, or EDBA plus a variety of known caspase inhibitors, and ganglion cell viability was assayed. EDBA killed 20-30% of ganglion cells. A general caspase inhibitor, BAF, prevented EDBA induced ganglion cell death. Specific inhibitors of caspase-3 and caspase-6 showed a similar ability to BAF in preventing EDBA mediated ganglion cell loss, whereas inhibitors of caspase-8 and caspase-9 were not able to rescue EDBA treated ganglion cells. A caspase-1,4 inhibitor was less effective than BAF. These studies show that a caspase mediated mechanism of apoptosis accents for a portion of EDBA mediated retinal ganglion cell death. This toxicity was mediated by downstream effector caspases, 3 and 6. Caspase inhibitors may prevent ganglion cell death secondary to ethambutol treatment.

Structure of 4,4'-[2,6-naphthylenebis(oxycarbonyl)]dibutyric acid

The molecules of the title compound are bonded along extended rows through hydrogen bonds between carboxylic groups. The packing of the rows shows a lateral matching of aromatic with aliphatic molecular sections.

The Role of the Phorbol Ester Receptor/Protein Kinase C in the Sensitivity of Leukemic Cells to Anthracyclines

The phorbol ester receptor (PER), which is believed to be identical to protein kinase C (PKC), has been implicated in the control of the sensitivities of tumor cells to certain forms of cancer chemotherapy. We evaluated the effects of regulating the expression of PER/PKC on the sensitivity of the R1B6 subclone of HL-60 human promyelocytic leukemic cells to anthracyclines. This cell line is resistant to the effects of phorbol esters on cellular differentiation by virtue of a down-regulated PER. R1B6 cells were maintained in phorbol 12, 13 dibutyric acid (PDBu). Twenty four to thirty six hours after removal of PDBu from the medium there was a 3-fold increase in the number of receptors compared to baseline values measured by [3H]-PDBu binding and a marked increase in the activity of PKC as measured by calcium-phospholipid dependent incorporation of [32P] into histone. Despite these changes in the number of PER and in the activity of PKC there was no difference in the cellular accumulation of [3H]-daunomycin or in the sensitivity of cells to the toxic effects of doxorubicin. Furthermore, there was no difference between the R1B6 cells and the parental HL-60 line in their intrinsic sensitivities to doxorubicin. These studies demonstrate that alterations in the expression of PER and the activity of PKC alone are not sufficient to influence anthracycline accumulation or toxicity in R1B6 human leukemic cells in contrast to recently reported results using other cell lines.

Quantitative determination of plasma hemoglobin using dicarboxidine

Since the demonstration of the potentially carcinogenic risk in workers using benzidine and o-tolidine, the use of these substances in laboratories has been limited. As a consequence of this there is a need for replacing these substances in, for example, the determination of plasma hemoglobin concentration. We have tested dicarboxidine, y,y’-(4,4’-diamino-3,3’-biphenylenedioxy)dibutyric acid dihydrochloride, which AB Kabi, Sweden has manufactured as a chromogenic reagent for quantitative determination of the hemoglobin concentration in plasma, instead of benzidine in the peroxidase reaction modified by Bing and Baker [ 11. This substance is considered much less carcinogenic than benzidine [2].

Metal binding by pharmaceuticals. Part 1. Copper(II) and zinc(II) interactions following ethambutol administration.

Formation constants for copper(II) and zinc(II) complexes of dextro-2,2'-(ethylenediimino)-di-1-butanol (ethambutol) and its metabolic oxidation product, 2,2'-(ethylenediimino)-dibutyric acid (EDBA) have been measured potentiometrically at 37 degrees C, I = 0.15 mol dm-3 [NaCl]. The constants are used in computer models to assess the extent of the formation of these complexes in vivo. These simulations indicate that whereas ethambutol forms metal complexes only to a limited extent in vivo, EDBA competes effectively under physiological conditions for copper(II) and zinc(II). This study suggests that zinc(II) binding by EDBA may account for a number of side effects of ethambutol treatment.

Dicarboxidine [γ,γ′-(4,4′-diamino-3,3′-biphenylylenedioxy)dibutyric acid] dihydrochloride as a chromogen for the detection of N-tert.-butyloxycarbonyl amino acids and peptides on thin-layer chromatograms

Dicarboxidine [γ,γ′-(4,4′-diamino-3,3′-biphenylylenedioxy)dibutyric acid] dihydrochloride as a chromogen for the detection of N-tert.-butyloxycarbonyl amino acids and peptides on thin-layer chromatograms

Dicarboxidine [γ,γ′-(4,4′-diamino-3,3′-biphenylylenedioxy)dibutyric acid] dihydrochloride as a chromogen for the detection of barbiturates, meprobamate and some other sedatives on thin-layer chromatograms

Dicarboxidine [γ,γ′-(4,4′-diamino-3,3′-biphenylylenedioxy)dibutyric acid] dihydrochloride as a chromogen for the detection of barbiturates, meprobamate and some other sedatives on thin-layer chromatograms

Dicarboxidine [γ, γ′-(4,4′-diamino-3,3′-biphenylylenedioxy)dibutyric acid] as a reagent for the spectrophotometric determination of cyanide and chlorine

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Oxidation of Thiacyclopentanone-2

Oxidation of thiacyclopentanone-2 with hydrogen peroxide gave γ, γ'-dithiodibutyric acid (1), dibutyric acid thiolsulfonate (2), and γ, γ'-sulfonyldibutyric acid (3) in 81%, 60% and 59% yields, respectively, under various reaction conditions.As an intermediate of this reaction, γ-mercaptobutyric acid was isolated.When the oxidation was carried out with dry chlorine gas or triacetone superoxide, only (1) was obtained in good yield and (2) and (3) was not detected.These results show that, the reaction of thiacyclopentanone-2 with hydrogen peroxide initially forms γ-mercaptobutyric acid, which is further oxidized to (3) via (1) and (2).

The crystal structure of l,4-piperazine-γ,γ'-dibutyric acid

The crystal structure of l,4-piperazine-γ,γ'-dibutyric acid

Comparative metabolism of ethambutol and its l-isomer

The absorption, excretion, and metabolism of the d- and l-isomers of 14C-labeled 2,2'-(ethylenediimino)-di-1-butanol have been studied. Both isomers disappear rapidly from the plasma after i.v. or oral administration in the dog, with the d-isomer being removed more rapidly from the circulation than the 1. The drug accumulates in or on the erythrocytes. Differences in the excretion of the two isomers also exist; 97% of an intravenous dose of the d-isomer is recovered from the excreta as compared with 81% of the dose of the l-isomer, Both isomers are metabolized by the dog to two compounds: (1) an intermediate metabolite aldehydic in nature and (2) a dicarboxylic acid -2,2'-(ethylenediimino)-di-butyric acid corresponding to the terminal oxidation product of the parent compound. The extent of metabolism of the l-isomer is greater than that of the d in the dog. Alcohol dehydrogenase and the soluble and microsomal fractions of rat liver convert the drug to an aldehyde, similar in nature to the primary metabolite.