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Dichloroacetic acid or trichloroacetic acid are commonly used in the detritylation reaction of the automated solid-phase synthesis of oligonucleotides. Dichloroacetic acid, however, is often contaminated with trichloroacetaldehyde (chloral), leading to the formation of inseparable impurities in the final oligonucleotide product. In this work, three different sequences, namely T 18 , d(TAA) 6 , and an 18-mer mixed sequence, were used as models to compare the deprotection efficiency of three acids: trichloroacetic acid, dichloroacetic acid, and difluoroacetic acid. Comparable purities of full-length products were obtained for the synthesis of the three model sequences when dichloroacetic acid or difluoroacetic acid were used during the detritylation reaction, however, conditions need to be optimized for the synthesis of purine-rich sequences. Therefore, difluoroacetic acid is a potential alternative to dichloroacetic acid in the solid-phase synthesis of oligonucleotides to avoid the impurity formation due to presence of chloral.

This study outlines a number of studies of dichloroacetic acid (DCA) and some of its derivatives. Although DCA has low cytotoxic potencies, various structural modifications are described which result in potent cytotoxins. In particular, hybrid molecules created from DCA and other bioactive molecules whose modes of action differ from DCA are particularly promising as candidate anticancer agents. Considerable emphasis in this review is placed on various series of compounds that incorporate both platinum and DCA into their structures. In addition, the importance of the formulation of some of the bioactive compounds described herein is revealed., (© 2022 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Dichloroacetate (DCA) commonly occurs in the environment due to natural production and anthropogenic releases, but its fate under anoxic conditions is uncertain. Mixed culture RM comprising " Candidatus Dichloromethanomonas elyunquensis" strain RM utilizes DCA as an energy source, and the transient formation of formate, H 2 , and carbon monoxide (CO) was observed during growth. Only about half of the DCA was recovered as acetate, suggesting a fermentative catabolic route rather than a reductive dechlorination pathway. Sequencing of 16S rRNA gene amplicons and 16S rRNA gene-targeted quantitative real-time PCR (qPCR) implicated " Candidatus Dichloromethanomonas elyunquensis" strain RM in DCA degradation. An ( S )-2-haloacid dehalogenase (HAD) encoded on the genome of strain RM was heterologously expressed, and the purified HAD demonstrated the cofactor-independent stoichiometric conversion of DCA to glyoxylate at a rate of 90 ± 4.6 nkat mg -1 protein. Differential protein expression analysis identified enzymes catalyzing the conversion of DCA to acetyl coenzyme A (acetyl-CoA) via glyoxylate as well as enzymes of the Wood-Ljungdahl pathway. Glyoxylate carboligase, which catalyzes the condensation of two molecules of glyoxylate to form tartronate semialdehyde, was highly abundant in DCA-grown cells. The physiological, biochemical, and proteogenomic data demonstrate the involvement of an HAD and the Wood-Ljungdahl pathway in the anaerobic fermentation of DCA, which has implications for DCA turnover in natural and engineered environments, as well as the metabolism of the cancer drug DCA by gut microbiota. IMPORTANCE Dichloroacetate (DCA) is ubiquitous in the environment due to natural formation via biological and abiotic chlorination processes and the turnover of chlorinated organic materials (e.g., humic substances). Additional sources include DCA usage as a chemical feedstock and cancer drug and its unintentional formation during drinking water disinfection by chlorination. Despite the ubiquitous presence of DCA, its fate under anoxic conditions has remained obscure. We discovered an anaerobic bacterium capable of metabolizing DCA, identified the enzyme responsible for DCA dehalogenation, and elucidated a novel DCA fermentation pathway. The findings have implications for the turnover of DCA and the carbon and electron flow in electron acceptor-depleted environments and the human gastrointestinal tract., (Copyright © 2021 Chen et al.)

The inevitable challenge in conventional chemotherapy is to deliver the anticancer drugs to the dense population of tumors cells while minimizing the drug-associated side effects on the normal cells. Cancer cells' preference for glycolysis for energy production is well recognized. Intuitively, taking advantage of such cancer-associated metabolism would be a promising strategy for anticancer drug delivery with minimal side effects. In this investigation, we have designed a binary prodrug PDOX as a sequential drug delivery regimens to realize the combination therapy for cancer. As cancer cells exhibit abrupt metabolism with elevated pyruvate dehydrogenase kinase (PDK) activity, dichloroacetic acid (DCA, a well-known PDK inhibitor) was used in combination with anticancer drug doxorubicin (DOX). The designed molecular prodrug was activated selectively by cancer-associated esterase to deliver DCA and DOX, respectively, and induced synergetic effects. Hence, sequential targeted delivery of molecular prodrug PDOX offers a promising approach to overcome the offside drug toxicity, pharmacokinetics, and biodistribution of individuals and provide an alternative option for cancer treatment.

Toxoplasmosis, a protozoan infection caused by Toxoplasma gondii , is estimated to affect around 2.5 billion people worldwide. Nevertheless, the side effects of drugs combined with the long period of therapy usually result in discontinuation of the treatment. New therapies should be developed by exploring peculiarities of the parasite's metabolic pathways, similarly to what has been well described in cancer cell metabolism. An example is the switch in the metabolism of cancer that blocks the conversion of pyruvate into acetyl coenzyme A in mitochondria. In this context, dichloroacetate (DCA) is an anticancer drug that reverts the tumor proliferation by inhibiting the enzymes responsible for this switch: the pyruvate dehydrogenase kinases (PDKs). DCA has also been used in the treatment of certain symptoms of malaria; however, there is no evidence of how this drug affects apicomplexan species. In this paper, we studied the metabolism of T. gondii and demonstrate that DCA also inhibits T. gondii 's in vitro infection with no toxic effects on host cells. DCA caused an increase in the activity of pyruvate dehydrogenase followed by an unbalanced mitochondrial activity. We also observed morphological alterations frequently in mitochondria and in a few apicoplasts, essential organelles for parasite survival. To date, the kinases that potentially regulate the activity of pyruvate metabolism in both organelles have never been described. Here, we confirmed the presence in the genome of two putative kinases ( T. gondii PDK [TgPDK] and T. gondii branched-chain α-keto acid dehydrogenase kinase [TgBCKDK]), verified their cellular localization in the mitochondrion, and provided in silico data suggesting that they are potential targets of DCA. IMPORTANCE Currently, the drugs used for toxoplasmosis have severe toxicity to human cells, and the treatment still lacks effective and safer alternatives. The search for novel drug targets is timely. We report here that the treatment of T. gondii with an anticancer drug, dichloroacetate (DCA), was effective in decreasing in vitro infection without toxicity to human cells. It is known that PDK is the main target of DCA in mammals, and this inactivation increases the conversion of pyruvate into acetyl coenzyme A and reverts the proliferation of tumor cells. Moreover, we verified the mitochondrial localization of two kinases that possibly regulate the activity of pyruvate metabolism in T. gondii , which has never been studied. DCA increased pyruvate dehydrogenase (PDH) activity in T. gondii , followed by an unbalanced mitochondrial activity, in a manner similar to what was previously observed in cancer cells. Thus, we propose the conserved kinases as potential regulators of pyruvate metabolism and interesting targets for new therapies., (Copyright © 2021 Ferrarini et al.)

Haloacetic acids (HAAs) were reported to be the most abundant category of DBPs in swimming pool water. In this study, the formation of HAAs from different organic precursors in swimming pool water, including UV filters, human body fluids, and natural organic matter (NOM), during chlorination was examined, and the effects of chlorine dose and halide concentrations on the formation of HAAs were evaluated. The results show that the total HAA yields from benzophenone-3 (BP-3) and Suwannee River humic acid (SRHA) were the highest among the nine organic precursors, and the yields of dichloroacetic acid and bromochloroacetic acid were higher than that of the other HAA species. In all the chlorinated samples of different organic precursors, longer chlorination time enhanced HAA formation. Both chlorine dose and bromide concentration significantly affected the formation of HAAs from BP-3 and SRHA during chlorination. With the increasing chlorine dose, the total HAA yields from SRHA and BP-3 significantly increased. Besides, the proportion of trihaloacetic acids (THAAs) rose while that of dihaloacetic acids (DHAAs) and monohaloacetic acids (MHAAs) declined with the increasing chlorine dose. With the increasing bromide concentration, HAA formation from SRHA increased while that of BP-3 decreased. The bromine incorporation factor (BIF) of the formed MHAAs, DHAAs and THAAs from SRHA and BP-3 both increased with the increasing bromide concentration in the following order: BIF DHAAs  > BIF THAAs  > BIF MHAAs , indicating that bromine was easier to be incorporated into DHAAs rather than MHAAs or THAAs. Moreover, bromide promoted the formation of Br-HAAs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Metal-organic frameworks (MOFs) are emerging as leading candidates for nanoscale drug delivery, as a consequence of their high drug capacities, ease of functionality, and the ability to carefully engineer key physical properties. Despite many anticancer treatment regimens consisting of a cocktail of different drugs, examples of delivery of multiple drugs from one MOF are rare, potentially hampered by difficulties in postsynthetic loading of more than one cargo molecule. Herein, we report a new strategy, multivariate modulation, which allows incorporation of up to three drugs in the Zr MOF UiO-66 by defect-loading. The drugs are added to one-pot solvothermal synthesis and are distributed throughout the MOF at defect sites by coordination to the metal clusters. This tight binding comes with retention of crystallinity and porosity, allowing a fourth drug to be postsynthetically loaded into the MOFs to yield nanoparticles loaded with cocktails of drugs that show enhancements in selective anticancer cytotoxicity against MCF-7 breast cancer cells in vitro. We believe that multivariate modulation is a significant advance in the application of MOFs in biomedicine, and anticipate the protocol will also be adopted in other areas of MOF chemistry, to easily produce defective MOFs with arrays of highly functionalised pores for potential application in gas separations and catalysis., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

A series of new fluoroquinolone conjugates 8a-g and 9a-f were synthesized via benzotriazole-mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against Escherichia coli and Staphylococcus aureus with potency higher than that of the parent drugs through in vitro standard bioassay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus, and Enterococcus faecalis, respectively). The observed experimental data were supported by enzymatic DNA gyrase inhibitory property. Developed BMLR-QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties., (© 2019 John Wiley & Sons Ltd.)

A novel class of hybrid molecules 2a-o was designed as candidate antineoplastic agents from dichloroacetic acid which is a known inhibitor of pyruvate dehydrogenase kinase and a number of cytotoxic 3,5-bis(benzylidene)-4-piperidones 1. In general these new hybrid molecules are potent cytotoxins towards human HCT116 colon cancer cells. A number of lead molecules emerged having the IC 50 values in the double digit nanomolar range. Most of these compounds are less toxic to human CRL1790 non-malignant colon cells and hence the selectivity index (SI) figures for most of the compounds are huge; in the case of 2c-g, m, n, the SI values are in excess of 100. Compounds 2g, 2j, 2m and 2n displayed >100-fold higher potency than the reference drug 5-FU. Quantitative structure-activity relationships revealed that the potencies of the compounds in series 2 increase as the magnitude of the Hammett σ and Taft σ* values rise. X-ray crystallographic of a representative compound 2c revealed various structural features which may influence cytotoxic potencies. Several representative compounds lowered the mitochondrial membrane potential and increased the production of reactive oxygen species in HCT116 cells. A minimal effect was noted in altering the percentage of cells in different phases of the cell cycle. Some futuredirections have been outlined for analog development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The reprogramming of energy metabolism is considered to be one of the main characteristics of cancer. The development of therapeutic agents targeting glycolysis to alter aberrant glucose metabolism and restore oxidative phosphorylation has emerged as an effective approach for cancer therapy. In this way, we have developed a conjugate AlbA-DCA, which can induce a marked increase in intracellular ROS and alleviate the accumulation of lactic acid in TME. Meanwhile, AlbA-DCA selectively kills cancer cells and exhibits an excellent synergistic effect. Mechanism studies confirm that AlbA-DCA can induce apoptosis and ferroptosis. We also confirm that AlbA-DCA can remold the tumor immunosuppression microenvironment via eliminating M2-TAMs to inhibit both primary and distal tumor progression in a dual-4T1 tumor model in female BALB/c mice. As a result, rational design of natural saponin and PDK inhibitor to induce apoptosis-ferroptosis-M2-TAMs polarization for enhanced cancer therapy is a promising strategy, thus providing a new idea for cancer therapy.

We herein describe the synthesis and characterization of the new amido-phosphinic ligand 3,7‑bis(dichloroacetyl)‑1,3,7‑triaza‑5‑phosphabicyclo[3.3.1]nonane (DCP), a derivative of dichloroacetic acid (DCA), whose ability to reverse the suppressed mitochondrial apoptosis in cancer cells is known. DCP was obtained by a double N-acylation of PTA (1,3,5‑triaza‑7‑phosphaadamantane) occurring with loss of CH 2 , in appropriate conditions . Due to the hindered rotation around the amidic CN bonds, three rotameric forms of DCP were observed, whose ratio in solution was dependent on the solvent, while the X-ray crystal structure of DCP showed an opposite orientation of the two amidic carbonyl groups (anti rotamer). The lipophilic, air and thermally stable DCP was found able to act regiospecifically as a P-donor ligand toward soft metal ions. By ligand substitution on appropriate precursors, we obtained the complexes 1-9, where proapoptotic DCA is associated with metal ions of known cytotoxic activity on cancer cells (Pt 2+ , Pd 2+ , Ru 2+ , Re + , Au + ). The antiproliferative activity of DCP and its complexes was tested in vitro, in comparison with cisplatin, on three human tumor cell lines: A2780 (ovarian cisplatin-sensitive), A2780cis (ovarian cisplatin-resistant) and K562 (erythroleukemic). The results showed that the simultaneous presence of DCP (containing two residues of proapoptotic DCA) and Pt(II) produces the best performances with respect to non-platinum complexes. Experiments of pro-apoptotic activity indicated that the antiproliferative activity of the most active DCP-Pt(II) complexes is associated with induction of apoptosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The purpose of this study was to develop liquid and solid paediatric formulations of sodium dichloroacetate (DCA) for the treatment of congenital lactic acidosis (CLA). In this work preformulation studies on the active molecule were performed to identify those physico-chemical properties of the drug relevant to the design of the dosage forms and their process of manufacture. TGA and DSC analysis suggested that sodium DCA was very hygroscopic. HPLC and NMR analysis showed that the compound was widely stable in aqueous solutions at 25 and 40 °C at all the pH values studied. Based on these results, sodium DCA was formulated as palatable solutions containing sweetener, viscosity enhancer and flavoring excipients tolerated by paediatric patients affected by CLA. The developed liquid formulations resulted chemically stable at 25 and 4 °C over three months. In use-stability tests showed no chemical degradation and microbiological contamination over one month. Oral tablets of sodium DCA were prepared by molding technique as an alternative and more practical formulation, easier to administer for caregivers than the liquid one. Technological assays (reported in the European Pharmacopeia) showed that oral tablets disaggregated quickly within 3 min at 25 °C in water, thus they were classified as orally disintegrating tablets. Preformulation studies provided a set of parameters against which detailed formulation design could be carried out. Formulation studies showed that the developed dosage forms achieved adequate stability, producibility and patient acceptability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase (PDK) that has been shown to reverse the Warburg effect and cause tumor cell death. Clinical research into the anti-cancer activity of DCA revealed high dosage requirements and reports of toxicity. While there have been subsequent mechanistic investigations, a search for DCA alternatives could result in a safer and more effective anticancer therapy. This study evaluates eight small compounds with a conserved dichloric terminal and their in vitro and in vivo potential for anticancer activity. Initial viability screening across six cancer cell lines reveals even at 10 mg/mL, compound treatments do not result in complete cell death which suggests minimal compound cytotoxicity. Furthermore, in vivo data demonstrates that cationic dichloric compounds DCAH and DCMAH, which were selected for further testing based on highest in vitro viability impact, inhibit tumor growth in the U87 model of glioblastoma, suggesting their clinical potential as accessible anti-cancer drugs. Immunoblotting signaling data from tumor lysates demonstrates that the mechanism of actions of cationic DCAH and DCMAH are unlikely to be consistent with that of the terminally carboxylic DCA and warrants further independent investigation.

This work aimed to optimize high-performance photocatalysts based on graphene oxide/titanium dioxide (GO/TiO 2 ) nanocomposites for the effective degradation of aqueous pollutants. The catalytic activity was tested against the degradation of dichloroacetic acid (DCA), a by-product of disinfection processes that is present in many industrial wastewaters and effluents. GO/TiO 2 photocatalysts were prepared using three different methods, hydrothermal, solvothermal, and mechanical, and varying the GO/TiO 2 ratio in the range of 1 to 10%. Several techniques were applied to characterize the catalysts, and better coupling of GO and TiO 2 was observed in the thermally synthesized composites. Although the results obtained for DCA degradation showed a coupled influence of the composite preparation method and its composition, promising results were obtained with the photocatalysts compared to the limited activity of conventional TiO 2 . In the best case, corresponding to the composite synthesized via hydrothermal method with 5% of GO/TiO 2 weight ratio, an enhancement of 2.5 times of the photocatalytic degradation yield of DCA was obtained compared to bare TiO 2 , thus opening more efficient ways to promote the application of photocatalytic remediation technologies.

Pyruvate dehydrogenase kinases (PDKs) dominate the critical switch between mitochondria-based respiration and cytoplasm-based glycolysis by controlling pyruvate dehydrogenase (PDH) activity. Up-regulated PDKs play a great role in the Warburg effect in cancer cells and accordingly present a therapeutic target. Dichloroacetate (DCA) and AZD7545 are the two most-well-known PDK inhibitors exhibiting distinct pharmacological profiles. DCA showed anticancer effects in various preclinical models and clinical studies, while the primary preclinical indication of AZD7545 was on the improvement of glucose control in type II diabetes. Little, if any, study has been undertaken the elucidation of the effects of PDK inhibition on the metabolites in the tricarboxylic acid (TCA) cycle. Herein, the metabolite alterations of lung cancer cells (A549) upon the treatment with PDK inhibitors were studied using a reliable liquid-chromatography-based tandem mass spectrometry method. The developed method was validated for quantification of all common glycolysis and TCA cycle catabolites with good sensitivity and reproducibility, including glucose, pyruvate, lactate, acetyl coenzyme A, citrate, α-ketoglutarate, fumarate, succinate, malate, and oxaloacetate. Our results suggested that A549 cells exhibited distinct metabolite profiles following the treatment with DCA or AZD7545, which may reflect the different pharmacological indications of these two drugs.

Cancer cell metabolism is quite different from normal cells. Targeting cancer metabolism and untuning the tumor metabolic machine has emerged as a promising strategy for cancer therapy. We have developed a multi-functional Re-dca conjugate (Re-dca 2) by conjugating the metabolic modulator dichloroacetate (DCA) to mitochondria-targeted rhenium(I) complex, allowing its efficient penetration into cancer cells and selective accumulation in mitochondria, thus achieving the cancer cell metabolism reversal from glycolysis to glucose oxidation at pharmacologically relevant DCA doses. Mechanism studies confirm the inhibition effect of Re-dca 2 on the activity of pyruvate dehydrogenase kinase (PDK) and capture the metabolic reversal window in Re-dca 2 treated NCI-1229 cells at the early stage of drug treatment, resulting in selective killing of malignant cells cocultured with normal cells, significant inhibition of cancer cell metastasis and invasion, as well as excellent anti-angiogenesis activities in zebrafish embryos. By comparison, DCA-free Re(I) analogue is also investigated under the same conditions. Although this analogue also exhibits cytotoxicity due to the Re(I) core, metabolic reversal is not induced by this analogue and its anti-metastasis activity is much lower than Re-dca 2, indicating the synergistic effect of Re(I) core and DCA moiety on cancer therapy. In vivo anti-cancer investigations also indicate that the mitochondria-targeted Re-dca 2 can effectively inhibit the tumor growth without affecting the body weight of nude mice, and the therapeutic effect is much better than the DCA-free Re(I) analogue 2a. Simultaneously, the O 2 -sensitive phosphorescent lifetimes of Re-dca 2 can be utilized for PLIM imaging of intracellular oxygen consumption, thus reflecting the Re-dca 2 induced glycolysis-to-glucose oxidation reversal at the early drug treatment stage. The excellent phosphorescence of Re-dca 2 can also be utilized for real-time tracking of mitochondrial morphological changes during treatment. In a word, rational design of phosphorescent metallodrug and metabolic modulator conjugates for synergistic treatment is a promising strategy for simultaneous untuning and tracking tumor metabolic machine, thus providing new clues for cancer therapy and mechanisms., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

With the aim to obtain dual acting drugs able to target both nuclear DNA and mitochondria, Pt(iv) kiteplatin derivatives having dichloroacetate (DCA) ligands in axial positions have been synthesized. The rather fast hydrolysis (t1/2 of ca. 1 h) and reduction (by ascorbic acid) of these Pt(iv) derivatives did not impede a potent pharmacological effect on tumor cells. Moreover, similarly to kiteplatin, also the Pt(iv)-DCA compounds proved to be capable of overcoming oxaliplatin-resistance, which is particularly important in view of the fact that metastatic colorectal cancer is the third most common cancer in males and the second in females. The possible role of DCA released by the Pt(iv) compounds in eliciting the antiproliferative activity has also been investigated. Pt(iv)-DCA compounds determine a substantial increase of ROS production, blockage of oxidative phosphorylation, hypopolarization of the mitochondrial membrane, and caspase-3/7 mediated apoptotic cell death.

Dual delivery of dichloroacetate and 5-fluorouracil from Zr MOFs into cancer cells is found to enhance in vitro cytotoxicity. Tuning particle size and, more significantly, surface chemistry, further improves cytotoxicity by promoting caveolae-mediated endocytosis and cytosolic cargo delivery.

Background: Doxorubicin (DOX) is an effective chemotherapeutic agent but severe side effects limit its clinical application. Nanoformulations can reduce the toxicity while still have various limitations, such as complexity, low drug loading capability and excipient related concerns., Methods: An amphiphilic conjugate, doxorubicin-dichloroacetate, was synthesized and the corresponding nanoparticles were prepared. The in vitro cytotoxicity and intracellular uptake, in vivo imaging, antitumor effects and systemic toxicities of nanoparticles were carried out to evaluate the therapeutic efficiency of tumor., Results: Doxorubicin-dichloroacetate conjugate can self-assemble into nanoparticles with small amount of DSPE-PEG 2000 , leading to high drug loading (71.8%, w/w) and diminished excipient associated concerns. The nanoparticles exhibited invisible systemic toxicity and high maximum tolerated dose of 75 mg DOX equiv./kg, which was 15-fold higher than that of free DOX. It also showed good tumor targeting capability and enhanced antitumor efficacy in murine melanoma model., Conclusion: This work provides a promising strategy to simplify the drug preparation process, increase drug loading content, reduce systemic toxicity as well as enhance antitumor efficiency., Competing Interests: Disclosure The author reports no conflicts of interest in this work.

We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η⁶- p cym)(bphen)(dca)]PF₆ ( Ru - dca ) and [Os(η⁶- p cym)(bphen)(dca)]PF₆ ( Os - dca ) containing dichloroacetate(1-) (dca) as the releasable O -donor ligand bearing its own cytotoxicity; p cym = 1-methyl-4-(propan-2-yl)benzene ( p -cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline). Complexes Ru - dca and Os-dca hydrolyzed in the water-containing media, which led to the dca ligand release (supported by ¹H NMR and electrospray ionization mass spectra). Mass spectrometry studies revealed that complexes Ru- dca and Os-dca do not interact covalently with the model proteins cytochrome c and lysozyme. Both complexes exhibited slightly higher in vitro cytotoxicity (IC 50 = 3.5 μM for Ru- dca , and 2.6 μM for Os-dca ) against the A2780 human ovarian carcinoma cells than cisplatin (IC 50 = 5.9 μM), while their toxicity on the healthy human hepatocytes was found to be IC 50 = 19.1 μM for Ru- dca and IC 50 = 19.7 μM for Os-dca . Despite comparable cytotoxicity of complexes Ru- dca and Os-dca , both the complexes modified the cell cycle, mitochondrial membrane potential, and mitochondrial cytochrome c release by a different way, as revealed by flow cytometry experiments. The obtained results point out the different mechanisms of action between the complexes., Competing Interests: The authors declare no conflict of interest.

Peroxides are one of the most important radicals that cause oxidative stress. Certain Glutathione S-transferases (GSTs) have been reported to show peroxidase activity. We report a novel peroxidase activity of Synechocystis GST- sll1545. The recombinant protein was purified to homogeneity and characterized. Low Km (0.109μM) and high Vmax (0.663μmolmin -1 ) values suggest a high preference of sll1545 for cumenehydroperoxide. Disc inhibition assay confirmed the ability of the enzyme to protect cells against peroxide-induced damage. sll1545 has very low sequence and structural similarity with theta and alpha class GSTs that exhibit glutathione-dependent peroxidase activity. Recent data from our laboratory shows that sll1545 is also strongly active against dichloroacetate (DCA), which is a characteristic of zeta class GST. Interestingly, sll1545 shows less than 20% sequence identity with zeta class GST. Molecular dynamic simulation results show that sll1545 was much more structurally different from alpha/theta classes. Our results suggest that sll1545 shows structural variation from zeta, theta/alpha classes of GSTs but have related enzymatic activity. Phylogenetic analysis reveal that sll1545 is evolutionally very distinct from the known GSTs. Overall, the data suggest that Synechocystis sll1545 does not belong to any known GST class and represent a novel GST class, which we have named rho., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Local recurrence following surgery in cancer treatment remains a major clinical challenge. To increase antitumor activity but maintain toxicity in an acceptable level in prevention of local cancer recurrence, we demonstrated a dual drug-loaded multilayered fiber mats strategy, in which DCA and oxaliplatin were co-electrospun into the distinct layer of resultant fabrics and the oxaliplatin-loaded fibers layer was sealed between the basement film layer and other two fibers layers. The dual drug-loaded multilayered fiber mats exhibit time-programmed dual release behavior and synergistic effect upon cancer cells. Nontoxic DCA selectively promotes apoptosis of cancer cells through modulating cellular metabolism, and oxaliplatin subsequently kills the remained cancer cells in a low concentration. After implantation on the resection margin of cervical carcinoma on a murine model, the dual drug-loaded multilayered fiber mats displayed enhanced anti-recurrence efficacy and decreased side toxic effects over 30days compared with drug-loaded monolayered fiber mats. The time-programmed combination of DCA and oxaliplatin within multilayered nanofiber mats appears to be a promising strategy for local cancer treatment following resection., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Pyruvate dehydrogenase kinases (PDKs) have recently emerged as an attractive target for cancer therapy. Herein, we prepared a series of compounds derived from dichloroacetate (DCA) which inhibited cancer cells proliferation. For the first time, we have successfully developed DCA derived inhibitors that preferentially bind to the adenosine triphosphate (ATP) pocket of PDK isoform 1 (PDK1).

Platinum agents can cause DNA damage and thus induce apoptosis of cancer cells, which has made them the backbone of cancer chemotherapy regimens. However, most cancers will develop drug resistance over the course of treatment. Meanwhile, most tumors meet energy needs largely by aerobic glycolysis (glycolysis in the presence of oxygen, called the Warburg effect), which is related to their resistance to apoptosis. Therefore, we have used a biodegradable polymer carrier to conjugate with DACH-Pt and dichloroacetate, a PDK inhibitor that can reverse the Warburg effect and derepress the resistance to apoptosis, thus sensitizing cancer cells to platinum. The as-prepared polymer-drug conjugates can be assembled into nanoparticles for effective delivery and better synergism. In vitro and in vivo studies revealed that the combination of polymer-DCA and polymer-DACH-Pt are much better than the free drugs administered simultaneously, in terms of both safety and antitumor efficacy.

Coagulation behavior of aluminum chloride and polyaluminum chloride (PACl) for removing corresponding disinfection byproduct (DBP) precursors was discussed in this paper. CHCl3, bromine trihalomethanes (THM-Br), dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) formation potential yields were correlated with specific ultraviolet absorbance (SUVA) values in different molecular weight (MW) fractions of humic substances (HS), respectively. Correlation analyses and principal component analysis were performed to examine the relationships between SUVA and different DBP precursors. To acquire more structural characters of DBP precursors and aluminum speciation, freeze-dried precipitates were analyzed by fourier transform infrared (FTIR) and C 1s, Al 2p X-ray photoelectron spectroscopy (XPS). The results indicated that TCAA precursors (no MW limits), DCAA and CHCl3 precursors in low MW fractions (MW<30 kDa) had a relatively good relations with SUVA values. These DBP precursors were coagulated more easily by in situ Al13 of AlCl3 at pH 5.0. Due to relatively low aromatic content and more aliphatic structures, THM-Br precursors (no MW limits) and CHCl3 precursors in high MW fractions (MW>30 kDa) were preferentially removed by PACl coagulation with preformed Al13 species at pH 5.0. Additionally, for DCAA precursors in high MW fractions (MW>30 kDa) with relatively low aromatic content and more carboxylic structures, the greatest removal occurred at pH 6.0 through PACl coagulation with aggregated Al13 species.

A biologically activate carbon (BAC) filter was continuously operated on site for the treatment of haloacetic acids (HAAs) in an outdoor swimming pool at an average empty bed contact time (EBCT) of 5.8 min. Results showed that BAC filtration was a viable technology for direct removal of HAAs from the pool water with a nominal efficiency of 57.7% by the filter while the chlorine residuals were 1.71 ± 0.90 mg/L during the study. THMs and TOC were not removed and thus were not considered as indicators of the effectiveness of BAC filtration. Increased EBCT in the range of 4.5 and 6.4 min led to improved HAA removal performance, which could be best fit by a logarithmic regression model. BAC filtration also affected the HAA speciation by removing more dichloroacetic acid (DCAA) than trichloroacetic acid (TCAA), resulting in a lower ratio of DCAA/TCAA in the filtered effluent. However, the observation of an overall constant ratio could be attributable to a complex formation and degradation mechanism occurring in swimming pools., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The mitochondrial kinase inhibitor dichloroacetate (DCA) has recently received attention in oncology due to its ability to target glycolysis. However, DCA molecule exhibits poor bioavailability and cellular uptake with limited ability to reach its target mitochondria. To overcome these biases, we have synthesized novel DCA-loaded compounds. The selection of the most promising therapeutic molecule was evaluated by combining in vitro assays, to test the antitumoral potential on leukemic cells, and a preliminary characterization of the molecule stability in vivo, in mice. Among the newly synthesized compounds, we have selected the multiple DCA-loaded compound 10, characterized by a tertiary amine scaffold, because it exhibited enhanced (>30-fold) in vitro antitumor activity with respect to DCA and increased in vivo stability. On the basis of these results, we believe that compound 10 should be considered for further preclinical evaluations for the treatment of cancers and/or other diseases characterized by altered metabolic origin.

1,2,3,4-Butanetetracarboxylic acid (BTCA) reacts with cellulose in two steps with catalysis of alkaline salts such as sodium hypophosphite: anhydride formation and esterification of anhydride with cellulose. The alkali metal ions were found effective in catalyzing formation of BTCA anhydride in a previous report. In this work, catalytic functions of the alkaline salts in the esterification reaction between BTCA anhydride and cellulose were investigated. Results revealed that acid anions play an important role in the esterification reaction by assisting removal of protons on intermediates and completion of the esterification between cellulose and BTCA. Besides, alkaline salts with lower pKa1 values of the corresponding acids are more effective ones for the reaction since addition of these salts could lead to lower pH values and higher acid anion concentrations in finishing baths. The mechanism explains the results of FTIR and wrinkle recovery angles of the fabrics cured under different temperatures and times., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

An ion chromatography method was developed for the simultaneous detection of three soluble herbicides (glyphosate, bentazone and picloram), three chlorine disinfection byproducts (monochloroacetic acid, dichloroacetic acid and trichloroacetic acid) and 12 anions in water (Cl(-), Br(-), SO4(2-), CO3(2-), ClO3(-), ClO4(-), BrO3(-), PO4(3-), NO2(-), NO3(-), CH3COO(-) and COO(-)). High linearity (r(2) > 0.996) was observed for all target analytes for each respective concentration range. The limit of detection and limit of quantitation were between 0.21-0.85 and 0.06-25.46 μg/L, respectively. However, the interference effect of Cl(-), NO3(-) , SO4 (2-) and CO3(2-) on some target analytes must be considered during the analysis. Sample pre-treatment by a hydrogen column (H-column) required to reduce the negative effect of CO3(2-). Additionally, sample pre-treatment by a sliver-hydrogen column (Ag-H-column) is required when Cl(-) > 100 mg/L and SO4(2-) < 50 mg/L, and pre-treatment by both a barium column (Ba-column) and an H-column is required when Cl(-) > 100 mg/L and SO4(2-) > 50 mg/L. When Cl(-) > 100 mg/L, SO4(2-) > 50 mg/L and CO3(2-) > 20 mg/L, the sample pre-treatment by either an Ag-H-Ba-column or an Ag-H-column and Ba-column is required to minimize interference., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pyruvate dehydrogenase complex (PDHC) is a key enzyme in metabolism linking glycolysis to tricarboxylic acid cycle and its activity is tightly regulated by phosphorylation catalyzed by four pyruvate dehydrogenase kinase (PDK) isoforms. PDKs are pharmacological targets for several human diseases including cancer, diabetes, obesity, heart failure, and inherited PDHC deficiency. We investigated the inhibitory activity of phenylbutyrate toward PDKs and found that PDK isoforms 1-to-3 are inhibited whereas PDK4 is unaffected. Moreover, docking studies revealed putative binding sites of phenylbutyrate on PDK2 and 3 that are located on different sites compared to dichloroacetate (DCA), a previously known PDK inhibitor. Based on these findings, we showed both in cells and in mice that phenylbutyrate combined to DCA results in greater increase of PDHC activity compared to each drug alone. These results suggest that therapeutic efficacy can be enhanced by combination of drugs increasing PDHC enzyme activity.

Defective oxidative phosphorylation has a crucial role in the attenuation of mitochondrial function, which confers therapy resistance in cancer. Various factors, including endogenous heat shock proteins (HSPs) and exogenous agents such as dichloroacetate, restore respiratory and other physiological functions of mitochondria in cancer cells. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents. Here, we summarize the key reasons contributing to mitochondria dysfunction in cancer cells and how restoration of mitochondrial function could be exploited for cancer therapeutics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Four new diam(m)ine platinum complexes containing the dichloroacetate moiety in 3-dichoroacetoxylcyclobutane-1,1-dicarboxylate as the leaving group were synthesized, characterized by elemental analysis as well as by ESI(+)-MS (electrospray ionization mass spectrometry in positive mode), FT-IR, (1)H- and (13)C-NMR, and evaluated for their in vitro anticancer activity against human lung cancer cell line (A549) and ovarian cancer cell lines (SK-OV-3, SK-OV-3/DDP). Diam(m)ines used in the present study belong to the carriers of six clinically approved platinum drugs. Among the complexes synthesized, complex 2, cis-[Pt(II)(1R,2R-diaminocyclohexane)·(3-dichoroacetoxylcyclobutane-1,1-dicarboxylate)] is the most promising in terms of water solubility and potential of being totally devoid of cross-drug resistance with cisplatin. Therefore, complex 2 was selected for the dichloroacetate release test. The test shows dichloroacetate can be efficiently released from complex 2 under physiological conditions via the hydrolysis of an ester bond bridging the dichloroacetate moiety and platinum pharmacophores together. Our study supports the further evaluation of this complex as a drug candidate., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Using a liquid-solid phase inversion method, a hybrid matrix poly(vinylidene fluoride) (PVDF) membrane was prepared with alumina (Al2O3) nanoparticle addition. Pd/Fe nanoparticles (NPs) were successfully immobilized on the Al2O3/PVDF membrane, which was characterized by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). The micrographs showed that the Pd/Fe NPs were dispersed homogeneously. Several important experimental parameters were optimized, including the mechanical properties, contact angle and surface area of Al2O3/PVDF composite membranes with different Al2O3 contents. At the same time, the ferrous ion concentration and the effect of hydrophilization were studied. The results showed that the modified Al2O3/PVDF membrane functioned well as a support. The Al2O3/PVDF membrane with immobilized Pd/Fe NPs exhibited high efficiency in terms of dichloroacetic acid (DCAA) dechlorination. Additionally, a reaction pathway for DCAA dechlorination by Pd/Fe NPs immobilized on the Al2O3/PVDF membrane system was proposed., (Copyright © 2015. Published by Elsevier B.V.)

The monochloroacetic, dichloroacetic and trichloroacetic acid (MCAA, DCAA and TCAA) removed by metallic iron under controlled dissolved oxygen conditions (0, 0.75, 1.52, 2.59, 3.47 or 7.09 mg/L DO) was investigated in well-mixed batch systems. The removal of CAAs increased first and then decreased with increasing DO concentration. Compared with anoxic condition, the reduction of MCAA and DCAA was substantially enhanced in the presence of O2, while TCAA reduction was significantly inhibited above 2.59 mg/L. The 1.52 mg/L DO was optimum for the formation of final product, acetic acid. Chlorine mass balances were 69-102%, and carbon mass balances were 92-105%. With sufficient mass transfer from bulk to the particle surface, the degradation of CAAs was limited by their reduction or migration rate within iron particles, which were dependent on the change of reducing agents and corrosion coatings. Under anoxic conditions, the reduction of CAAs was mainly inhibited by the available reducing agents in the conductive layer. Under low oxic conditions, the increasing reducing agents and thin lepidocrocite layer were favorable for CAA dechlorination. Under high oxic conditions, the redundant oxygen competing for reducing agents and significant lepidocrocite growth became the major restricting factors. Various CAA removal mechanisms could be potentially applied to explaining the effect of DO concentration on iron efficiency for contaminant reduction in water and wastewater treatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Differences in energy metabolism between tumor cells and normal cells offer an attractive avenue of research into drug targets for tumor therapy. The use of a metabolic modulator (sodium dichloroacetate, DCA), administered in situ, to reverse the "Warburg effect" of tumor cells has been demonstrated as an effective tumor therapy. Herein, DCA and diisopropylamine dichloroacetate (DADA) were incorporated separately into polylactide (PLA) electrospun mats and applied to C26 tumor-bearing mice via in situ administration. After 12 d of treatment, the tumor suppression rates of 75% and 84% were achieved in the DC group (treated with a DCA-loaded mat) and the DA group (treated with a DADA-loaded mat), respectively. With tolerable physiologic toxicity under high local concentration, the DA group showed a 95% tumor suppression rate without any recurrence after 15 d of therapy. The desirable therapeutic effects of these metabolic modulators should ascribe to the energy-central metabolism-targeting effects of DCA and DADA, which were demonstrated both in vitro and in vivo. Therefore, DCA- and DADA-loaded mats are the effective anti-cancer drugs dosages to discriminate between tumor cells and normal cells for minimizing systemic toxicity.

Background: C9, a newly in silico-designed inhibitor of microtubule dynamics induces G2/M arrest culminating in apoptosis. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase, an enzyme that promotes pyruvate entry into mitochondria. The use of antitumor drugs targeting different cancer features can be a more effective way to overcome drug resistance., Methods: The influence of C9 (130 nM) + DCA (7.5 mM) on MCF-7 and MCF-12 cells was assessed via microscopy spectrophotometry global gene expression and flow cytometry assays., Results: An LDH assay showed that C9+DCA treatment decreased cell viability to 83.5% in MCF-7 cells when compared to the non-tumorigenic MCF-12A cells 92.4% (P < 0.05). C9- and C9+DCA treatment induced mitochondrial membrane potential depolarization in MCF-7 cells but not in MCF-12A cells (P < 0.05). The occurrence of apoptosis was associated with increased hypo- and hyper-phosphorylation of Bcl-2 Ser(70) and caspase 7 activation. Kinase inhibition revealed sustained activation of the JNK pathway caused increased Bcl-2 protein Ser(70) hypo-and hyper-phosphorylation. Elevated levels of DCF fluorescence was observed in DCA-, C9- and C9+DCA-exposed MCF-7 cells, but not in MCF-12A cells, indicating cytosolic H₂O₂/Fe(2+) formation in treated tumorigenic cells. LC3-II expression was elevated in C9+DCA-treated cells in both cell lines, indicating that autophagy was also induced., Conclusions: Synergistic effects of C9+DCA were demonstrated on breast carcinoma and non-tumorigenic cells with selectivity towards the MCF-7 cells. Antimitotic compound C9 in combination with a glycolytic inhibitor dichloroacetate eradicates breast cancer cells through ROS-JNK-Bcl-2-mediated signalling pathways in vitro and it is argued that autophagy acts as protective mechanism in the treated cells before apoptosis occurs., (© 2015 S. Karger AG, Basel.)

Dichloroacetate (DCA) is a water purification byproduct that is known to be hepatotoxic and hepatocarcinogenic and to induce peripheral neuropathy and damage macrophages. This study characterizes the effects of the haloacetate on lung cells by exposing rat alveolar type II (L2) cells to 0-24 mM DCA for 6-24 hours. Increasing DCA concentration and the combination of increasing DCA concentration plus longer exposures decrease measures of cellular health. Length of exposure has no effect on oxidative stress biomarkers, glutathione, SOD, or CAT. Increasing DCA concentration alone does not affect total glutathione or its redox ratio but does increase activity in the SOD/CAT oxidative stress defense pathway. These data suggest that alveolar type II cells rely on SOD and CAT more than glutathione to combat DCA-induced stress.

Dissolved organic matter (DOM) represents the major pool of organic precursors for harmful disinfection byproducts, such as haloacetic acids (HAAs), formed during drinking water chlorination, but much of it remains molecularly uncharacterized. Knowledge of model precursors is thus a prerequisite for understanding the more complex whole water DOM. The utility of HAA formation potential data from model DOM precursors, however, is limited due to the lack of comparability to water samples. In this study, the formation kinetics of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), the two predominant HAA species, were delineated upon chlorination of seventeen model DOM precursors and sixty-eight inland lake water samples collected from the Upper Midwest region of the United States. Of particular interest was the finding that the DCAA and TCAA formation rate constants could be grouped into four statistically distinct clusters reflecting the core structural features of model DOM precursors (i.e., non-β-diketone aliphatics, β-diketone aliphatics, non-β-diketone phenolics, and β-diketone phenolics). A comparative approach built upon hierarchical cluster analysis was developed to gain further insight into the chlorine reactivity patterns of HAA precursors in inland lake waters as defined by the relative proximity to four model precursor clusters. This work highlights the potential for implementing an integrated kinetic-clustering approach to constrain the chlorine reactivity of DOM in source waters.

The direct incorporation of chloramines and dissolved organic nitrogen (DON) may provide the nitrogen for nitrogenous disinfection byproducts (N-DBPs). This study explores the contributions of natural DON and chloramine incorporation to the formation of N-DBPs during chloramination. This study also evaluates the relationship between N-DBPs and carbonaceous DBPs by investigating four sources of dissolved organic matter with different DON-to-dissolved organic carbon (DOC) ratios. During chloramination, dihaloacetonitrile (DXAN) formation is correlated with the summation of trihalomethanes (THMs) and dichloroacetic acids (DXAAs) yield in molar basis at pH > 6. This study tests the formation kinetics of THMs, DXAAs, and DXANs during chloramination, explores the changes in DBP formation potential before and after a sequence of ozonation and chloramination, and tracks the nitrogen source of dichloroacetonitrile. The results support the hypothesis that THMs, DXAAs, and DXANs mainly derive from similar precursors upon chloramination. In addition, the precursor of HANs was approximately 10% (on a molar basis) of that of THMs and HAAs combined. The N-nitrosodimethylamine (NDMA) formation potential is correlated with DON/DOC in hydrophilic and transphilic fractions. Isotope (15)N-labeled monochloramine coupled with LC-electrospray ionization-tandem mass spectrometry was used to explore the nitrogen source of NDMA formed in chloraminated organic fractions. The results indicate that the nitroso group of the formed NDMA originates mainly from chloramines., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

An innovative haloacetic acid (HAA) removal process was developed. The process consisted of a zero-valent iron (Fe(0)) column followed by a biologically active carbon (BAC) column that were efficient in degrading tri- and di-HAAs, and mono- and di-HAAs, respectively. The merit of the process was demonstrated by its performance in removing trichloroacetic acid (TCAA). An empty bed contact time of 10 min achieved nearly complete removal of 1.2 μM TCAA and its subsequent products, dichloroacetic acid (DCAA) and monochloroacetic acid (MCAA). HAA removal was a result of chemical dehalogenation and biodegradation rather than physical adsorption. Preliminary kinetic analyses were conducted and the pseudo-first-order rate constants were estimated at ambient conditions for Fe(0) reduction of TCAA and biodegradation of DCAA and MCAA by BAC. This innovative process is highly promising in removing HAAs from drinking water, swimming pool water, and domestic or industrial wastewater., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A theoretical study was performed to examine hydrogen and halogen bonds properties in gas phase and crystalline dichloroacetic acid (DCAA). The specific pattern of O-H∙∙∙O, C-H∙∙∙O, HCl, Cl∙∙∙O and Cl∙∙∙Cl interactions in DCAA dimers is described within the quantum theory of atoms in molecules (QTAIM) formalism. Based on QTAIM results, a partial covalent character is attributed to the O-H∙∙∙O hydrogen bonds in DCAA, whereas all the C-H∙∙∙O, Cl···O and Cl∙∙∙Cl intermolecular interactions are weak and basically electrostatic in nature. MP2/6-311++G** calculations indicate that the interaction energies for DCAA dimers lie in the range between -0.40 and -14.58 kcal mol(-1). One of the most important results of this study is that, according to energy decomposition analyses, halogen bonds are largely dependent on both electrostatic and dispersion interactions. For those nuclei participating in the hydrogen-bonding and halogen-bonding interactions, nuclear quadrupole coupling constants exhibit significant changes on going from the isolated molecule model to the crystalline DCAA. Of course, the magnitude of these changes at each nucleus depends directly on its amount of contribution to the interactions.

A multifunctional hybrid platinum(IV) prodrug, which consists of both the mitochondria-targeting drug DCA and the DNA-crosslinking drug cisplatin, was synthesized and tethered to a carrier polymer to further self-assemble into micelles for intracellular delivery.

The bacterial signaling molecule, cyclic diguanosine monophosphate (c-di-GMP), plays a key role in controlling biofilm formation and pathogenic virulence, among many other functions. It has widespread consequences for human health, and current research is actively exploring its molecular mechanisms. The convenient one-flask, gram-scale synthesis of c-di-GMP described here will facilitate these efforts.

The performance of a heterogeneous photocatalytic ozonation system (TiO(2)/UVA/O(3)) was evaluated on the degradation and mineralization of dichloroacetic acid as a contaminant in aqueous solutions by means of a planar reactor. The commercial product "Pilkington Active™ glass" was used as the immobilized TiO(2) photocatalyst and it was irradiated by near UV light in this study. The synergistic interaction between ozone and the photoactivated TiO(2) surface was discussed and highlighted. Furthermore, the influences of initial concentration and temperature on the degradation rate of dichloroacetic acid and the ozone consumption level during the oxidation process were investigated. The concentrations of dichloroacetic acid and chloride anions produced during degradation were measured using ion chromatography. The mineralization of dichloroacetic acid was evaluated by Total Organic Carbon (TOC) measurements. The degradation of dichloroacetic acid by photocatalytic ozonation showed good agreement with the kinetics of first-order reactions with respect to dichloroacetic acid.

Objectives:   To investigate anti-proliferative properties of a novel in silico-modelled 17β-oestradiol derivative (C9), in combination with dichloroacetic acid (DCA), on MCF-7 and MCF-12A cells., Materials and Methods:   xCELLigence system was employed to determine optimal seeding number for cells, and crystal violet assay was used to assess cell number and to determine IC(50) value (24 h) for combination treatment. Light and fluorescent microscopy techniques were used to morphologically detect types of cell death. Flow cytometry was used to analyse cell cycle and apoptosis., Results:   Optimal seeding number for 96-well plates was determined to be 5000-10 000 cells/well for both MCF-7 and MCF-12A cells. IC(50) for MCF-7 cells of the combination treatment after 24 h was 130 nm of C9 in conjunction with 7.5 mm of DCA (P < 0.05). In contrast, the same concentration inhibited cell population growth by only 29.3% for MCF-12As after 24-h treatment (P < 0.05). Morphological studies revealed lower cell density of both types of combination-treated cells. Flow cytometric analyses demonstrated increase in sub-G(1) phase in combination-treated MCF-7 cells., Conclusions:   These results demonstrate that the novel 17β-oestradiol derivative C9, in combination with DCA is a potent anti-proliferation treatment, with properties of selectivity towards tumourigenic cells. Thus, this warrants further studies as a potential combination chemotherapeutic agent for further cancer cell lines., (© 2011 Blackwell Publishing Ltd.)

Acidic aqueous solutions of the chlorinated aliphatic hydrocarbons 1,2-dichloroethane (DCA) and 1,1,2,2-tetrachloroethane (TCA) have been treated by the electro-Fenton (EF) process. Bulk electrolyses were performed at constant current using a BDD anode and an air diffusion cathode able to generate H(2)O(2) in situ, which reacts with added Fe(2+) to yield OH from Fenton's reaction. At 300 mA, almost total mineralization was achieved at 420 min for solutions containing 4mM of either DCA or TCA. Comparative treatments without Fe(2+) (anodic oxidation) or with a Pt anode led to a poorer mineralization. The better performance of the EF process with BDD is explained by the synergistic action of the oxidizing radicals, BDD(OH) at the anode surface and OH in the bulk, and the minimization of diffusional limitations. The decay of the initial pollutant accomplished with pseudo first-order kinetics. Chloroacetic and dichloroacetic acids were the major by-products during the degradation of DCA and TCA, respectively. Acetic, oxalic and formic acids were also identified. The proposed reaction pathways include oxidative and reductive (cathodic) dechlorination steps. Chlorine was released as Cl(-), being further oxidized to ClO(3)(-) and, mostly, to ClO(4)(-), due to the action of the largely generated BDD(OH) and OH., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Chloroacetic acids, formed during the disinfection process in potable water production, are considered to pose a potential risk to human health. This article deals with dichloroacetic acid (DCAA) removal from drinking water by using a process of bentonite based adsorptive ozonation. This process is formed by combined addition of ozone, bentonite and Fe(3+). During the reaction, DCAA is removed by the joint effect of adsorption, ozonation and catalytic oxidation. In addition, under the effect of the adsorption, natural organic matters (NOM) can be adsorbed onto the bentonite surface, resulting in a reduced scavenging effect toward HO· radicals, and hence eliminate the negative effect of NOM on DCAA removal. At the initial stage of the reaction, Fe(3+) is rapidly hydrolyzed to polycations and adsorbed onto the bentonite surface or into its structural layers. This positively charges the surface of the bentonite and increases its surface area, resulting in a strong adsorption of HA or DCAA. Furthermore, Fe(3+) catalyzes ozone decomposition to form HO· thus further improving the efficiency. The adsorptive ozonation has been shown to be potentially advantageous in destruction of toxic, dissolved pollutants in drinking water, and appears to have great potential for a wide range of treatment applications.

This work focuses on conjugating the anti-cancer drug dichloroacetic acid (DCA) to the monocyte/macrophage targeting protein hemoglobin (Hb). The DCA-Hb conjugate carries approximately 12 DCA molecules per Hb tetramer, and binds to haptoglobin (Hp) forming stable DCA-Hb-Hp complexes, in a similar manner to unmodified Hb. The results of this study show that DCA-Hb-Hp is taken up by the monocytic cancer cell line THP-1, where it depolarizes the mitochondrial membrane potential, thereby inhibiting cancerous cell growth at a comparable level to free DCA. Taken together, the results of this study show promise for the use of the DCA-Hb conjugate as a potential therapeutic to treat monocytic leukemia., (Copyright © 2011 Wiley Periodicals, Inc.)

Various conditions for optimum detritylation (i.e., the removal of 5'-O-trityl protecting groups) during solid-phase synthesis of oligodeoxyribonucleotides were investigated. Di- and tri-chloroacetic acids of variable concentrations were used to study the removal of the 4,4'-dimethoxytrityl (DMTr) group. It was found that the DMTr group could be completely removed under much milder acidic conditions than what are currently used for automated solid-phase synthesis. The 2,7-dimethylpixyl (DMPx) is proposed as an alternative and more readily removable group for the protection of the 5'-OH functions both in solid- and solution-phase synthesis. The improved detritylation conditions are expected to minimize the waste and offer a protocol for incorporation of acid sensitive building-blocks in oligonucleotides.

Dichloroacetate (DCA) is a potential environmental hazard and an investigational drug. Repeated doses of DCA result in reduced drug clearance, probably through inhibition of glutathione transferase ζ1 (GSTZ1), a cytosolic enzyme that converts DCA to glyoxylate. DCA is known to be taken up by mitochondria, where it inhibits pyruvate dehydrogenase kinase, its major pharmacodynamic target. We tested the hypothesis that the mitochondrion was also a site of DCA biotransformation. Immunoreactive GSTZ1 was detected in liver mitochondria from humans and rats, and its identity was confirmed by liquid chromatography/tandem mass spectrometry analysis of the tryptic peptides. Study of rat submitochondrial fractions revealed GSTZ1 to be localized in the mitochondrial matrix. The specific activity of GSTZ1-catalyzed dechlorination of DCA was 2.5- to 3-fold higher in cytosol than in whole mitochondria and was directly proportional to GSTZ1 protein expression in the two compartments. Rat mitochondrial GSTZ1 had a 2.5-fold higher (App)K(m) for glutathione than cytosolic GSTZ1, whereas the (App)K(m) values for DCA were identical. Rats administered DCA at a dose of 500 mg/kg/day for 8 weeks showed reduced hepatic GSTZ1 activity and expression of ∼10% of control levels in both cytosol and mitochondria. We conclude that the mitochondrion is a novel site of DCA biotransformation catalyzed by GSTZ1, an enzyme colocalized in cytosol and mitochondrial matrix.