Cytotoxic derivatives of dichloroacetic acid and some metal complexes.

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.

Anaerobic Microbial Metabolism of Dichloroacetate.

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, H2, 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.

Dichloroacetate and Pyruvate Metabolism: Pyruvate Dehydrogenase Kinases as Targets Worth Investigating for Effective Therapy of Toxoplasmosis.

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.

Binary Prodrug of Dichloroacetic Acid and Doxorubicin with Enhanced Anticancer Activity.

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.

Multivariate Modulation of the Zr MOF UiO-66 for Defect-Controlled Combination Anticancer Drug Delivery.

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.

Formation of haloacetic acids from different organic precursors in swimming pool water during chlorination.

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: BIFDHAAs > BIFTHAAs > BIFMHAAs, indicating that bromine was easier to be incorporated into DHAAs rather than MHAAs or THAAs. Moreover, bromide promoted the formation of Br-HAAs.

Design, synthesis, antimicrobial, and DNA gyrase inhibitory properties of fluoroquinolone-dichloroacetic acid hybrids.

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.

Novel hybrid molecules of 3,5-bis(benzylidene)-4-piperidones and dichloroacetic acid which demonstrate potent tumour-selective cytotoxicity.

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 IC50 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.

Natural Product Albiziabioside A Conjugated with Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate To Induce Apoptosis-Ferroptosis-M2-TAMs Polarization for Combined Cancer Therapy.

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.

A new amido-phosphine of dichloroacetic acid as an active ligand for metals of pharmaceutical interest. Synthesis, characterization and tests of antiproliferative and pro-apoptotic activity.

We herein describe the synthesis and characterization of the new amido-phosphinic ligand 3,7­bis(dichloroacetyl)­1,3,7­triaza­5­phosphabicyclo[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 (1,3,5­triaza­7­phosphaadamantane) occurring with loss of CH2, 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 (Pt2+, Pd2+, Ru2+, 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.

Two dichloric compounds inhibit in vivo U87 xenograft tumor growth.

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.

Pharmaceutical preformulation studies and paediatric oral formulations of sodium dichloroacetate.

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.

Liquid Chromatography-Tandem Mass Spectrometry Method Revealed that Lung Cancer Cells Exhibited Distinct Metabolite Profiles upon the Treatment with Different Pyruvate Dehydrogenase Kinase Inhibitors.

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.

Targeted reversal and phosphorescence lifetime imaging of cancer cell metabolism via a theranostic rhenium(I)-DCA conjugate.

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 O2-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.

Dual-acting antitumor Pt(iv) prodrugs of kiteplatin with dichloroacetate axial ligands.

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.

A facile doxorubicin-dichloroacetate conjugate nanomedicine with high drug loading for safe drug 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-PEG2000, 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.

Enhancing anticancer cytotoxicity through bimodal drug delivery from ultrasmall Zr MOF nanoparticles.

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.

Half-Sandwich Ru(II) and Os(II) Bathophenanthroline Complexes Containing a Releasable Dichloroacetato Ligand.

We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η6-pcym)(bphen)(dca)]PF6 (Ru-dca) and [Os(η6-pcym)(bphen)(dca)]PF6 (Os-dca) containing dichloroacetate(1-) (dca) as the releasable O-donor ligand bearing its own cytotoxicity; pcym = 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 (IC50 = 3.5 µM for Ru-dca, and 2.6 µM for Os-dca) against the A2780 human ovarian carcinoma cells than cisplatin (IC50 = 5.9 µM), while their toxicity on the healthy human hepatocytes was found to be IC50 = 19.1 µM for Ru-dca and IC50 = 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.

Enhanced photocatalytic activity using GO/TiO2 catalyst for the removal of DCA solutions.

This work aimed to optimize high-performance photocatalysts based on graphene oxide/titanium dioxide (GO/TiO2) 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/TiO2 photocatalysts were prepared using three different methods, hydrothermal, solvothermal, and mechanical, and varying the GO/TiO2 ratio in the range of 1 to 10%. Several techniques were applied to characterize the catalysts, and better coupling of GO and TiO2 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 TiO2. In the best case, corresponding to the composite synthesized via hydrothermal method with 5% of GO/TiO2 weight ratio, an enhancement of 2.5 times of the photocatalytic degradation yield of DCA was obtained compared to bare TiO2, thus opening more efficient ways to promote the application of photocatalytic remediation technologies.

A combined biochemical and computational studies of the rho-class glutathione s-transferase sll1545 of Synechocystis PCC 6803.

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.