Study on Design, Synthesis and Herbicidal Activity of Novel 6-Indazolyl-2-picolinic Acids.

Thirty-eight new 4-amino-3,5-dicholo-6-(1H-indazolyl)-2-picolinic acids and 4-amino-3,5-dicholo-6-(2H-indazolyl)-2-picolinic acids were designed by scaffold hopping and synthesized to discover potential herbicidal molecules. All the new compounds were tested to determine their inhibitory activities against Arabidopsis thaliana and the root growth of five weeds. In general, the synthesized compounds exhibited excellent inhibition properties and showed good inhibitory effects on weed root growth. In particular, compound 5a showed significantly greater root inhibitory activity than picloram in Brassica napus and Abutilon theophrasti Medicus at the concentration of 10 µM. The majority of compounds exhibited a 100% post-emergence herbicidal effect at 250 g/ha against Amaranthus retroflexus and Chenopodium album. We also found that 6-indazolyl-2-picolinic acids could induce the up-regulation of auxin genes ACS7 and NCED3, while auxin influx, efflux and auxin response factor were down-regulated, indicating that 6-indazolyl-2-picolinic acids promoted ethylene release and ABA production to cause plant death in a short period, which is different in mode from other picolinic acids.

Exploring the in vitro anticancer activities of Re(I) picolinic acid and its fluorinated complex derivatives on lung cancer cells: a structural study.

Fifteen rhenium(I) tricarbonyl complexes of the form fac-[Re(N,O')(CO)3(X)], where N,O'-bidentate ligand = 2-picolinic acid (Pico); 3,5-difluoropyridine-2-carboxylic acid (Dfpc); 3-trifluoromethyl-pyridine-2-carboxylic acid (Tfpc) and X = H2O; pyrazole (Pz); pyridine (Py); imidazole (Im); and methanol (CH3OH) were synthesized using the '2 + 1' mixed ligand approach with an average yield of 84%. The complexes were characterized using the following spectroscopic techniques: IR, 1H and 13C NMR, UV/Vis, and single-crystal X-ray diffraction. The effect of the fluorine atoms on the backbone of the N,O'-bidentate ligand was investigated and a trend was noticed in the carbonyl stretching frequencies: with Pico < Tfpc < Dfpc. The in vitro biological screening on Vero (healthy mammalian), HeLa (cervical carcinoma) and A549 (lung cancer) cells revealed one toxic complex, fac-[Re(Pico)(CO)3(H2O)], with respective LC50 values of 9.0 ± 0.9, 15.8 ± 4.9 (SI = 0.570) and 20.9 ± 0.8 (SI = 0.430) µg/mL. As a result, it can be used as a positive control drug of toxicity.

Picolinic Acid-Mediated Catalysis of Mn(II) for Peracetic Acid Oxidation Processes: Formation of High-Valent Mn Species.

Metal-based advanced oxidation processes (AOPs) with peracetic acid (PAA) have been extensively studied to degrade micropollutants (MPs) in wastewater. Mn(II) is a commonly used homogeneous metal catalyst for oxidant activation, but it performs poorly with PAA. This study identifies that the biodegradable chelating ligand picolinic acid (PICA) can significantly mediate Mn(II) activation of PAA for accelerated MP degradation. Results show that, while Mn(II) alone has minimal reactivity toward PAA, the presence of PICA accelerates PAA loss by Mn(II). The PAA-Mn(II)-PICA system removes various MPs (methylene blue, bisphenol A, naproxen, sulfamethoxazole, carbamazepine, and trimethoprim) rapidly at neutral pH, achieving >60% removal within 10 min in clean and wastewater matrices. Coexistent H2O2 and acetic acid in PAA play a negligible role in rapid MP degradation. In-depth evaluation with scavengers and probe compounds (tert-butyl alcohol, methanol, methyl phenyl sulfoxide, and methyl phenyl sulfone) suggested that high-valent Mn species (Mn(V)) is a likely main reactive species leading to rapid MP degradation, whereas soluble Mn(III)-PICA and radicals (CH3C(O)O• and CH3C(O)OO•) are minor reactive species. This study broadens the mechanistic understanding of metal-based AOPs using PAA in combination with chelating agents and indicates the PAA-Mn(II)-PICA system as a novel AOP for wastewater treatment.

Peroxymonosulfate Activation by Fe(III)-Picolinate Complexes for Efficient Water Treatment at Circumneutral pH: Fe(III)/Fe(IV) Cycle and Generation of Oxyl Radicals.

Improving the reactivity of Fe(III) for activating peroxymonosulfate (PMS) at circumneutral pH is critical to propel the iron-activated PMS processes toward practical wastewater treatment but is yet challenging. Here we employed the complexes of Fe(III) with the biodegradable picolinic acid (PICA) to activate PMS for degradation of selected chlorinated phenols, antibiotics, pharmaceuticals, herbicides, and industrial compounds at pH 4.0-6.0. The FeIII-PICA complexes greatly outperformed the ligand-free Fe(III) and other Fe(III) complexes of common aminopolycarboxylate ligands. In the main activation pathway, the key intermediate is a peroxymonosulfate complex, tentatively identified as PICA-FeIII-OOSO3-, which undergoes O-O homolysis or reacts with FeIII-PICA and PMS to yield FeIV=O and SO4•- without the involvement of commonly invoked Fe(II). PICA-FeIII-OOSO3- can also react directly with certain compounds (chlorophenols and sulfamethoxazole). The relative contributions of PICA-FeIII-OOSO3-, FeIV=O, and SO4•- depend on the structure of target compounds. This work sets an eligible example to enhance the reactivity of Fe(III) toward PMS activation by ligands and sheds light on the previously unrecognized role of the metal-PMS complexes in directing the catalytic cycle and decontamination as well.

Design, Synthesis, Herbicidal Activity, and Structure-Activity Relationship Study of Novel 6-(5-Aryl-Substituted-1-Pyrazolyl)-2-Picolinic Acid as Potential Herbicides.

Picolinic acid and picolinate compounds are a remarkable class of synthetic auxin herbicides. In recent years, two new picolinate compounds, halauxifen-methyl (ArylexTM active) and florpyrauxifen-benzyl (RinskorTM active), have been launched as novel herbicides. Using their structural skeleton as a template, 33 4-amino-3,5-dicholor-6-(5-aryl-substituted-1-pytazolyl)-2-picolinic acid compounds were designed and synthesized for the discovery of compounds with potent herbicidal activity. The compounds were tested for inhibitory activity against the growth of Arabidopsis thaliana roots, and the results demonstrated that the IC50 value of compound V-7 was 45 times lower than that of the halauxifen-methyl commercial herbicide. Molecular docking analyses revealed that compound V-7 docked with the receptor auxin-signaling F-box protein 5 (AFB5) more intensively than picloram. An adaptive three-dimensional quantitative structure-activity relationship model was constructed from these IC50 values to guide the next step of the synthetic strategy. Herbicidal tests of the new compounds indicated that compound V-8 exhibited better post-emergence herbicidal activity than picloram at a dosage of 300 gha-1, and it was also safe for corn, wheat, and sorghum at this dosage. These results demonstrated that 6-(5-aryl-substituted-1-pyrazolyl)-2-picolinic acid compounds could be used as potential lead structures in the discovery of novel synthetic auxin herbicides.

PicR as a MarR Family Transcriptional Repressor Multiply Controls the Transcription of Picolinic Acid Degradation Gene Cluster pic in Alcaligenes faecalis JQ135.

Picolinic acid (PA) is a natural toxic pyridine derivative as well as an important intermediate used in the chemical industry. In a previous study, we identified a gene cluster, pic, that responsible for the catabolism of PA in Alcaligenes faecalis JQ135. However, the transcriptional regulation of the pic cluster remains known. This study showed that the entire pic cluster was composed of 17 genes and transcribed as four operons: picR, picCDEF, picB4B3B2B1, and picT1A1A2A3T2T3MN. Deletion of picR, encoding a putative MarR-type regulator, greatly shortened the lag phase of PA degradation. An electrophoretic mobility shift assay and DNase I footprinting showed that PicR has one binding site in the picR-picC intergenic region and two binding sites in the picB-picT1 intergenic region. The DNA sequences of the three binding sites have the palindromic characteristics of TCAG-N4-CTNN: the space consists of four nonspecific bases, and the four palindromic bases on the left and the first two palindromic bases on the right are strictly conserved, while the last two bases on the right vary among the three binding sites. An in vivo ß-galactosidase activity reporter assay indicated that 6-hydroxypicolinic acid but not PA acted as a ligand of PicR, preventing PicR from binding to promoter regions and thus derepressing the transcription of the pic cluster. This study revealed the negative transcriptional regulation mechanism of PA degradation by PicR in A. faecalis JQ135 and provides new insights into the structure and function of the MarR-type regulator. IMPORTANCE The pic gene cluster was found to be responsible for PA degradation and widely distributed in Alpha-, Beta-, and Gammaproteobacteria. Thus, it is very necessary to understand the regulation mechanism of the pic cluster in these strains. This study revealed that PicR binds to three sites of the promoter regions of the pic cluster to multiply regulate the transcription of the pic cluster, which enables A. faecalis JQ135 to efficiently utilize PA. Furthermore, the study also found a unique palindrome sequence for binding of the MarR-type regulator. This study enhanced our understanding of microbial catabolism of environmental toxic pyridine derivatives.

Synthesis and Evaluation of Novel 111In-Labeled Picolinic Acid-Based Radioligands Containing an Albumin Binder for Development of a Radiotheranostic Platform.

Picolinic acid-based metallic chelators, e.g., neunpa and octapa, have attracted much attention as promising scaffolds for radiotheranostic agents, particularly those containing larger α-emitting radiometals. Furthermore, albumin binder (ALB) moieties, which noncovalently bind to albumin, have been utilized to improve the pharmacokinetics of radioligands targeting various biomolecules. In this study, we designed and synthesized novel neunpa and octapa derivatives (Neunpa-2 and Octapa-2, respectively), which contained a prostate-specific membrane antigen (PSMA)-binding moiety (model targeting vector) and an ALB moiety. We evaluated the fundamental properties of these derivatives as radiotheranostic agents using 111In. In a cell-binding assay using LNCaP (PSMA-positive) cells, [111In]In-Neunpa-2 and [111In]In-Octapa-2 specifically bound to the LNCaP cells. In addition, a human serum albumin (HSA)-binding assay revealed that [111In]In-Neunpa-2 and [111In]In-Octapa-2 exhibited greater binding to HSA than their non-ALB-conjugated counterparts ([111In]In-Neunpa-1 and [111In]In-Octapa-1, respectively). A biodistribution assay conducted in LNCaP tumor-bearing mice showed that the introduction of the ALB moiety into the 111In-labeled neunpa and octapa derivatives resulted in markedly enhanced tumor uptake and retention of the radioligands. Furthermore, single-photon emission computed tomography imaging of LNCaP tumor-bearing mice with [111In]In-Octapa-2 produced tumor images. These results indicate that [111In]In-Octapa-2 may be a useful PSMA imaging probe and that picolinic acid-based ALB-conjugated radiometallic complexes may be promising candidates as radiotheranostic agents.

Enhanced Degradation of Micropollutants in a Peracetic Acid-Fe(III) System with Picolinic Acid.

Activation of peracetic acid (PAA) with iron species is an emerging advanced oxidation process (AOP). This study investigates the use of the chelating agent picolinic acid (PICA) to extend the pH range and enhance the performance of the PAA-Fe(III) AOP. Compared to the PAA-Fe(III) system, the PAA-Fe(III)-PICA system degrades various micropollutants (MPs: methylene blue, naproxen, sulfamethoxazole, carbamazepine, trimethoprim, diclofenac, and bisphenol-A) much more rapidly at higher pH, achieving almost complete removal of parent compounds within 10 min. PAA significantly outperforms the coexistent H2O2 and is the key oxidant for rapid compound degradation. Other chelating agents, EDTA, NTA, citric acid, proline, and nicotinic acid, could not enhance MP degradation in the PAA-Fe(III) system, while 2,6-pyridinedicarboxylic acid with a structure similar to PICA moderately enhanced MP degradation. Experiments with scavengers (tert-butyl alcohol and methyl phenyl sulfoxide) and a probe compound (benzoic acid) confirmed that high-valent iron species [Fe(IV) and/or Fe(V)], rather than radicals, are the major reactive species contributing to MP degradation. The oxidation products of methylene blue, naproxen, and sulfamethoxazole by PAA-Fe(III)-PICA were characterized and supported the proposed mechanism. This work demonstrates that PICA is an effective complexing ligand to assist the Fenton reaction of PAA by extending the applicable pH range and accelerating the catalytic ability of Fe(III).

The Fenton Reaction in Water Assisted by Picolinic Acid: Accelerated Iron Cycling and Co-generation of a Selective Fe-Based Oxidant.

The Fenton reaction is limited by a narrow acidic pH range, the slow reduction of Fe(III), and susceptibility of the nonselective hydroxyl radical (HO•) to scavenging by water constituents. Here, we employed the biodegradable chelating agent picolinic acid (PICA) to address these concerns. Compared to the classical Fenton reaction at pH 3.0, PICA greatly accelerated the degradation of atrazine, sulfamethazine, and various substituted phenols at pH 5.0 in a reaction with autocatalytic characteristics. Although HO• served as the principal oxidant, a high-spin, end-on hydroperoxo intermediate, tentatively identified as PICA-FeIII-OOH, also exhibited reactivity toward several test compounds. Chloride release from the oxidation of 2,4,6-trichlorophenol and the positive slope of the Hammett correlation for a series of halogenated phenols were consistent with PICA-FeIII-OOH reacting as a nucleophilic oxidant. Compared to HO•, PICA-FeIII-OOH is less sensitive to potential scavengers in environmental water samples. Kinetic analysis reveals that PICA facilitates Fe(III)/Fe(II) transformation by accelerating Fe(III) reduction by H2O2. Autocatalysis is ascribed to the buildup of Fe(II) from the reduction of Fe(III) by H2O2 as well as PICA oxidation products. PICA assistance in the Fenton reaction may be beneficial to wastewater treatment because it favors iron cycling, extends the pH range, and balances oxidation universality with selectivity.

The Solvent Effect on Composition and Dimensionality of Mercury(II) Complexes with Picolinic Acid.

Three new mercury(II) coordination compounds, {[HgCl(pic)]}n (1), [HgCl(pic)(picH)] (2), and [HgBr(pic)(picH)] (3) (picH = pyridine-2-carboxylic acid, picolinic acid) were prepared by reactions of the corresponding mercury(II) halides and picolinic acid in an aqueous (1) or alcohol-methanol or ethanol (2 and 3) solutions. Two different types of coordination compounds were obtained depending on the solvent used. The crystal structures were determined by the single-crystal X-ray structural analysis. Compound 1 is a one-dimensional (1-D) coordination polymer with mercury(II) ions bridged by chelating and bridging N,O,O'-picolinate ions. Each mercury(II) ion is four-coordinated with a bidentate picolinate ion, a carboxylate O atom from the symmetry-related picolinate ion and with a chloride ion; the resulting coordination environment can be described as a highly distorted tetrahedron. Compounds 2 and 3 are isostructural mononuclear coordination compounds, each mercury(II) ion being coordinated with the respective halide ion, N,O-bidentate picolinate ion, and N,O-bidentate picolinic acid in a highly distorted square-pyramidal coordination environment. Compounds 1-3 were characterized by IR spectroscopy, PXRD, and thermal methods (TGA/DSC) in the solid state and by 1H and 13C NMR spectroscopy in the DMSO solution.

Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-ß-lactamase-1.

New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.

Thorium chelators for targeted alpha therapy: Rapid chelation of thorium-226.

One of the main challenges in targeted alpha therapy is assuring delivery of the α-particle dose to the targeted cells. Thus, it is critical to identify ligands for α-emitting radiometals that will form complexes that are very stable, both in vitro and in vivo. In this investigation, thorium-227 (t1/2 = 18.70 days) chelation of ligands containing hydroxypyridinonate (HOPO) or picolinic acid (pa) moieties and the stability of the resultant complexes were studied. Chelation reactions were followed by reversed-phased HPLC and gamma spectroscopy. Studies revealed that high 227 Th chelation yields could be obtained within 2.5 h or less with ligands containing four Me-3,2-HOPO moieties, 1 (83%) and 2 (65%), and also with ligands containing pa moieties, H4 octapa 3 (65%) and H4 py4pa 6 (87%). No reaction occurred with H4 neunpa-p-Bn-NO2 4, and the chelation reaction with another pa ligand H4 pypa 5 gave inconsistent yields with a very broad radio-HPLC peak. The ligands spermine-(Me-3,2-HOPO)4 1, H4 octapa 3, and H4 py4pa 6 had high stability (i.e., 87% of 227 Th still bound to the ligand) in phosphate-buffered saline at room temperature over a 6-day period. Preliminary studies with ligand 6 demonstrated efficient chelation of thorium-226 (t1/2 = 30.57 min) when heated to 80°C for 5 min.

Identification and Characterization of a Novel pic Gene Cluster Responsible for Picolinic Acid Degradation in Alcaligenes faecalis JQ135.

Picolinic acid (PA) is a natural toxic pyridine derivative. Microorganisms can degrade and utilize PA for growth. However, the full catabolic pathway of PA and its physiological and genetic foundation remain unknown. In this study, we identified a gene cluster, designated picRCEDFB4B3B2B1A1A2A3, responsible for the degradation of PA from Alcaligenes faecalis JQ135. Our results suggest that PA degradation pathway occurs as follows: PA was initially 6-hydroxylated to 6-hydroxypicolinic acid (6HPA) by PicA (a PA dehydrogenase). 6HPA was then 3-hydroxylated by PicB, a four-component 6HPA monooxygenase, to form 3,6-dihydroxypicolinic acid (3,6DHPA), which was then converted into 2,5-dihydroxypyridine (2,5DHP) by the decarboxylase PicC. 2,5DHP was further degraded to fumaric acid through PicD (2,5DHP 5,6-dioxygenase), PicE (N-formylmaleamic acid deformylase), PicF (maleamic acid amidohydrolase), and PicG (maleic acid isomerase). Homologous pic gene clusters with diverse organizations were found to be widely distributed in Alpha-, Beta-, and Gammaproteobacteria Our findings provide new insights into the microbial catabolism of environmental toxic pyridine derivatives.IMPORTANCE Picolinic acid is a common metabolite of l-tryptophan and some aromatic compounds and is an important intermediate in organic chemical synthesis. Although the microbial degradation/detoxification of picolinic acid has been studied for over 50 years, the underlying molecular mechanisms are still unknown. Here, we show that the pic gene cluster is responsible for the complete degradation of picolinic acid. The pic gene cluster was found to be widespread in other Alpha-, Beta-, and Gammaproteobacteria These findings provide a new perspective for understanding the catabolic mechanisms of picolinic acid in bacteria.

Novel 3,6-Dihydroxypicolinic Acid Decarboxylase-Mediated Picolinic Acid Catabolism in Alcaligenes faecalis JQ135.

Picolinic acid (PA), a typical C-2-carboxylated pyridine derivative, is a metabolite of l-tryptophan and many other aromatic compounds in mammalian and microbial cells. Microorganisms can degrade and utilize PA for growth. However, the precise mechanism of PA metabolism remains unknown. Alcaligenes faecalis strain JQ135 utilizes PA as its carbon and nitrogen source for growth. In this study, we screened a 6-hydroxypicolinic acid (6HPA) degradation-deficient mutant through random transposon mutagenesis. The mutant hydroxylated 6HPA into an intermediate, identified as 3,6-dihydroxypicolinic acid (3,6DHPA), with no further degradation. A novel decarboxylase, PicC, was identified to be responsible for the decarboxylation of 3,6DHPA to 2,5-dihydroxypyridine. Although, PicC belonged to the amidohydrolase 2 family, it shows low similarity (<45%) compared to other reported amidohydrolase 2 family decarboxylases. Moreover, PicC was found to form a monophyletic group in the phylogenetic tree constructed using PicC and related proteins. Further, the genetic deletion and complementation results demonstrated that picC was essential for PA degradation. The PicC was Zn2+-dependent nonoxidative decarboxylase that can specifically catalyze the irreversible decarboxylation of 3,6DHPA to 2,5-dihydroxypyridine. The Km and kcat toward 3,6DHPA were observed to be 13.44 µM and 4.77 s-1, respectively. Site-directed mutagenesis showed that His163 and His216 were essential for PicC activity. This study provides new insights into the microbial metabolism of PA at molecular level.IMPORTANCE Picolinic acid is a natural toxic pyridine derived from l-tryptophan metabolism and other aromatic compounds in mammalian and microbial cells. Microorganisms can degrade and utilize picolinic acid for their growth, and thus a microbial degradation pathway of picolinic acid has been proposed. Picolinic acid is converted into 6-hydroxypicolinic acid, 3,6-dihydroxypicolinic acid, and 2,5-dihydroxypyridine in turn. However, there was no physiological and genetic validation for this pathway. This study demonstrated that 3,6-dihydroxypicolinic acid was an intermediate in picolinic acid catabolism and further identified and characterized a novel amidohydrolase 2 family decarboxylase PicC. PicC was also shown to catalyze the decarboxylation of 3,6-dihydroxypicolinic acid into 2,5-dihydroxypyridine. This study provides a basis for understanding picolinic acid degradation and its underlying molecular mechanism.

Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications.

In the last 30 years, since the discovery that vanadium is a cofactor found in certain enzymes of tunicates and possibly in mammals, different vanadium-based drugs have been developed targeting to treat different pathologies. So far, the in vitro studies of the insulin mimetic, antitumor and antiparasitic activity of certain compounds of vanadium have resulted in a great boom of its inorganic and bioinorganic chemistry. Chemical speciation studies of vanadium with amino acids under controlled conditions or, even in blood plasma, are essential for the understanding of the biotransformation of e.g. vanadium antidiabetic complexes at the physiological level, providing clues of their mechanism of action. The present article carries out a bibliographical research emphaticizing the chemical speciation of the vanadium with different amino acids and reviewing also some other important aspects such as its chemistry and therapeutical applications of several vanadium complexes.

Toxicity and cardiac effects of acute exposure to tryptophan metabolites on the kynurenine pathway in early developing zebrafish (Danio rerio) embryos.

Defects in tryptophan metabolism on the l-kynurenine pathway (KP) are implicated in a number of human diseases, including chronic kidney disease, brain edema or injury, tuberculosis and malaria - as well as cancer, neurodegenerative and autoimmune disorders. However, it is unclear to what extent detrimental effects of exposure to tryptophan metabolites might impact the early development of organism. Thus, this study examined the effects of KP exposure in zebrafish embryos starting at the blastula period (4hpf) and the segmentation stage (24hpf). 24-hour EC50 and LC50 values were determined in 4hpf embryos as: 26.74 and 331.6µM for anthranilic acid (AA), 62.88 and 616.4µM for quinolinic acid (QUIN), and EC50 - 96.10µM for picolinic acid (PA) and LC50 - 400µM in kynurenic acid (KYNA). In addition, treatment with nanomolar concentrations of KYNA (50nM, 48 and 72hpf embryos) caused a dose-dependent increase in heartbeat. The increase was also seen with l-kyn treatment (50µM, 72hpf), which was the opposite of other applied l-kyn metabolites. A significant drop in heartbeat was observed after a 20-min acute exposure to 626µM PA, 594µM XA and 499µM QUIN, and complete recovery was seen only when PA had been removed. Concentrations of KP metabolites reached in people with different pathological conditions did not exert toxicity to zebrafish embryos and seems to be safe for developing embryos and therefore, the risk of developing impairments in pregnancy of women carrying KP-associated pathologies is initially low.

Biodegradation of 5-chloro-2-picolinic acid by novel identified co-metabolizing degrader Achromobacter sp. f1.

Several bacteria have been isolated to degrade 4-chloronitrobenzene. Degradation of 4-chloronitrobenzene by Cupriavidus sp. D4 produces 5-chloro-2-picolinic acid as a dead-end by-product, a potential pollutant. To date, no bacterium that degrades 5-chloro-2-picolinic acid has been reported. Strain f1, isolated from a soil polluted by 4-chloronitrobenzene, was able to co-metabolize 5-chloro-2-picolinic acid in the presence of ethanol or other appropriate carbon sources. The strain was identified as Achromobacter sp. based on its physiological, biochemical characteristics, and 16S rRNA gene sequence analysis. The organism completely degraded 50, 100 and 200 mg L-1 of 5-chloro-2-picolinic acid within 48, 60, and 72 h, respectively. During the degradation of 5-chloro-2-picolinic acid, Cl- was released. The initial metabolic product of 5-chloro-2-picolinic acid was identified as 6-hydroxy-5-chloro-2-picolinic acid by LC-MS and NMR. Using a mixed culture of Achromobacter sp. f1 and Cupriavidus sp. D4 for degradation of 4-chloronitrobenzen, 5-chloro-2-picolinic acid did not accumulate. Results infer that Achromobacter sp. f1 can be used for complete biodegradation of 4-chloronitrobenzene in remedial applications.

The kynurenine pathway of tryptophan degradation is activated during osteoblastogenesis.

The mechanisms involved in the anabolic effect of interferon gamma (IFNγ) on bone have not been carefully examined. Using microarray expression analysis, we found that IFNγ upregulates a set of genes associated with a tryptophan degradation pathway, known as the kynurenine pathway, in osteogenic differentiating human mesenchymal stem cells (hMSC). We, therefore, hypothesized that activation of the kynurenine pathway plays a role in osteoblastogenesis even in the absence of IFNγ. Initially, we observed a strong increase in tryptophan degradation during osteoblastogenesis with and without IFNγ in the media. We next blocked indoleamine 2,3-dioxygenase-1 (IDO1), the most important enzyme in the kynurenine pathway, using a siRNA and pharmacological approach and observed a strong inhibition of osteoblastogenesis with a concomitant decrease in osteogenic factors. We next examined the bone phenotype of Ido1 knockout (Ido1(-/-)) mice. Compared to their wild-type littermates, Ido1(-/-) mice exhibited osteopenia associated with low osteoblast and high osteoclast numbers. Finally, we tested whether the end products of the kynurenine pathway have an osteogenic effect on hMSC. We identified that picolinic acid had a strong and dose-dependent osteogenic effect in vitro. In summary, we demonstrate that the activation of the kynurenine pathway plays an important role during the commitment of hMSC into the osteoblast lineage in vitro, and that this process can be accelerated by exogenous addition of IFNγ. In addition, we found that mice lacking IDO1 activity are osteopenic. These data therefore support a new role for the kynurenine pathway and picolinic acid as essential regulators of osteoblastogenesis and as potential new targets of bone-forming cells in vivo.

Investigation into the Synthesis, Bioactivity, and Mechanism of Action of the Novel 6-Pyrazolyl-2-picolinic Acid as a Herbicide.

A series of new 4-amino-3,5-dicholo-6-(5-aryl-substituted-1H-pyrazol-1-yl)-2-picolinic acid compounds were designed and prepared to discover herbicidal molecules. The inhibitory activities of all new compounds against the root growth ofArabidopsis thaliana were assayed. On the whole, the new synthesized compounds displayed good inhibition effects and had excellent herbicidal activities on root growth of weed at 500 µM. Importantly, a selection of compounds demonstrated comparable herbicidal properties to picloram. At the dosage of 250 g/ha, most of the compounds showed a 100% postemergence herbicidal activity to control Chenopodium album and Amaranthus retroflexus. Using compound V-2, the mechanism of action was investigated based on a phenotype study using AFB5-deficient Arabidopsis thaliana. It was found that the novel 6-pyrazolyl-2-picolinic acids were auxinic compounds. In addition, it was proposed that V-2 may be an immune activator due to its upregulation of defense genes and the increased content of jasmonic acid.

Eight-day fasting modulates serum kynurenines in healthy men at rest and after exercise.

Introduction: Tryptophan's (Trp) metabolites are undervalued markers of human health. Their serum concentrations are modified by physical exercise and other factors, among which fasting has a well-documented role. Although this mechanism is hardly explored, thus, the study aimed to determine the effect of the 8-day fasting period and the impact of such a procedure on a single bout of an endurance exercise on the concentration of kynurenine pathway (KP) metabolites. Methods: 10 participants fasted for 8 days, and 10 as a control group participated in the study. The exercise was performed at baseline after an overnight fast and repeated post 8 days. Results: The 8 days of fasting increased the resting 3-hydroxy-L-kynurenine (3HK), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA) serum concentration. Also elevated phenylalanine (Phe) and tyrosine (Tyr) levels were recorded, suggesting expanded proteolysis of muscle proteins. In turn, physical activity caused a decrease in the concentration of 3-hydroxyanthranilic acid (3HAA) and PA after fasting. The obtained results were not recorded in controls. Conclusion: The results of this study show that the health-promoting effects of fasting are associated with changes in the KYN pathway. The increase in the concentration of PA and XA metabolites following fasting is capable of penetrating the blood-brain barrier, and KYNA, which initiates several beneficial changes, supports this assumption.