Picolinic Acid Derivatives Research Articles

Repression of autocrine pheromone signaling leads to fusaric acid over-production

Fusaric acid (FA), a picolinic acid derivative, is a natural substance produced by a wide variety of fungal plant pathogens belonging to the Fusarium genus. As a metabolite, fusaric acid exerts several biological activities including metal chelation, electrolyte leakage, repression of ATP synthesis, and direct toxicity on plants, animals and bacteria. Prior studies on the structure of fusaric acid revealed a co-crystal dimeric adduct between FA and 9,10-dehydrofusaric acid. During an ongoing search for signaling genes differentially regulating FA production in the fungal pathogen Fusarium oxysporum (Fo), we found that mutants lacking pheromone expression have an increased production of FA compared to the wild type strain. Noteworthy, crystallographic analysis of FA extracted from Fo culture supernatants showed that crystals are formed by a dimeric form of two FA molecules (1:1 molar stoichiometry). Overall, our results suggest that pheromone signaling in Fo is required to regulate the synthesis of fusaric acid.

Preparation and diagnosis of new picolinic acid derivatives

In this study, a new series of heterocyclic rings derived from picolinic acid was prepared. The quaternary reaction of acid hydrazone with chloroacetyl chloride was intended to obtain the azitidine-2-on ring known as beta-lactam and the preparation of the seventh ring of acid hydrazone reaction with the anhydride and phthalic anhydride To obtain a 3.1-oxabine loop. The five-ring of the picolinic acid hydrazide reaction with CS2 was also destined to obtain a 4,3,1-oxadiazole-2-thaion ring. The new compounds were diagnosed using FT-IR techniques and resonance technique Nuclear Magnetic H-NMR and 13C-NMR.

Synthesis of picolinates via a cooperative vinylogous anomeric-based oxidation using UiO-66(Zr)-N(CH2PO3H2)2 as a catalyst.

The anomeric effect highlights the significant influence of the functional group and reaction conditions on oxidation-reduction. This article successfully investigates the anomeric effect in the synthesis of picolinate and picolinic acid derivatives through a multi-component reaction involving 2-oxopropanoic acid or ethyl 2-oxopropanoate, ammonium acetate, malononitrile, and various aldehydes. To facilitate this process, we employed UiO-66(Zr)-N(CH2PO3H2)2 as a novel nanoporous heterogeneous catalyst. The inclusion of phosphorous acid tags on the UiO-66(Zr)-N(CH2PO3H2)2 offers the potential for synthesizing picolinates at ambient temperature.

Shared Hydrogen Atom Location and Chemical Composition in Picolinic Acid and Pyridoxal Hydrochloride Derivatives Determined by X-ray Crystallography.

Three new single-crystal structures were isolated for picolinic acid (2), the trifluoroacetate salt of picolinic acid (1), and pyridoxal hydrochloride (3). These compounds displayed unconventional crystallographic features that must be considered when structural refinements are carried out. Thus, the generated Fourier differences map obtained with the diffraction data collected at 100 K was crucial to visualize electron densities, which were balanced by either one hydrogen atom or a hydrogen atom with an occupancy factor of 1/2 located between either two carboxylate moieties, two phenolic oxygen atoms, or two pyridinic nitrogen atoms. Moreover, NMR studies were conducted to analyze the bulk chemical composition of single crystals of 2-pyridinecarboxylic acid obtained from the gem-diol/hemiacetal forms and the polymerization products after the treatment of 2-pyridinecarboxaldehyde with TFA:H2O (1) or a diluted Cu(NO3)2 solution (2). The quantitative yield of the pyridoxal hydrochloride crystalline material (3) obtained from a diluted CuCl2 solution was exhaustively characterized by solid-state NMR methods. These methods allowed the resolution of the signals corresponding to the protons of the hydroxyl moiety of the intramolecular hemiacetal group and the phenolic hydrogen. Theoretical calculations using DFT methods were done to complement the atomic location of the hydrogen atoms obtained from the X-ray analysis.

Synthesis and optoelectronic properties of a dinuclear iridium (III) complex containing a picolinic acid derivative by nonconjugated linkage with a D-A-D core

A novel dinuclear iridium (Ⅲ) complex containing a non- conjugated bridging picolinic acid ligand of (C8TPAPhOC2FIrpic)2BT with a D-A-D core was synthesized and characterized, in which the D-A-D core consists of benzo[c][1,2,5]thiadiazole (BT) and triphenylamino (TPA) units. Its optophysical, electrochemical and electroluminescent characteristics were primarily studied. It is found this dinuclear iridium (Ⅲ) complex exhibited similar photoluminescent and electroluminescent profiles, but higher brightness and efficiency in compared with the picolinic acid ligand in the single-emissive-layer organic light-emitting devices. The maximum luminance of 7404 cd/m2 and current efficiency of 0.81 cd/A was obtained in the (C8TPAPhOC2FIrpic)2BT-based devices. The efficient energy transfer is observed from the terminal iridium complex unit to the picolinic acid ligand. This work demonstrates that the picolinic acid ligand with a D-A-D core can facilitate dinuclear iridium (III) complex to exhibit the ancillary ligand-based red emission.

Interaction of V(V) complexes formed by picolinic and pyrazinecarboxylic acid derivatives with red blood cells

The interaction with red blood cells (RBC) of vanadium(V) complexes formed by 3,5-difluoropicolinic acid (HpicFF), 3-hydroxypicolinic acid (H2hypic) and pyrazinecarboxylic acid (Hprz) has been examined. Electron Paramagnetic Resonance (EPR) spectroscopy results suggest that V(V) is reduced in all cases to V(IV) inside the erythrocytes. The thermodynamic stability of V(V) and corresponding V(IV) complexes has been related with the species detected in the cellular environment; when the ligands form unstable complexes with both VVO2+ and VIVO2+ ions (picFF and prz), the species formed inside RBC are similar to those observed when starting with vanadate(V) alone, that is VIVO2+ – formed upon V(V) reduction – which distributes among the cellular bioligands forming different types of complexes. When in the ligand molecule other groups able to form chelated complexes are present (H2hypic), more stable species are formed inside the RBC. The amount of complex able to enter the RBC depends on the ligand structure which could influence the metal uptake. The interaction of different VIVO2+ complexes formed by picolinate (picFF, pic = picolinate, picCN = 5-cyanopicolinate) and pyrazinecarboxylate (prz and przNH2 = 3-aminopyrazine-2-carboxylate) derivatives with hemoglobin (Hb), which is the main candidate to bind the VIVO2+ ion in the cytosol, was also investigated to rationalize the results. The ligands which form at physiological pH relatively stable complexes with VIVO2+ (przNH2 and pic) can give inside the erythrocytes mixed species after the replacement of an equatorial water molecule by an imidazole nitrogen of a histidine residue of the protein, while the ligands which form with VIVO2+ unstable complexes (picCN, picFF, prz) yield the same species observed in the binary system VIVO2+–Hb.

WITHDRAWN: New picolinic acid derivatives: Synthesis, docking study and anti-EGFR kinase inhibitory effect

Abstract New derivatives (4A-4D) were designed and synthesized from, picolinic acid (PA). The newly synthesized compounds were confirmed by ATR-FTIR, 1HNMRS, 13CNMR and CHNS analysis. The molecular docking methodology of (4A-4D) against EGFR kinase revealed that certain compounds occupied the vital site of EGFR kinase pocket and with a good fit. By employing the MTT assay, it was found that. compound 4C has anti-tumor activity against MCF-7 breast cancer cell line (GI50 = 86.8 µg/mL), but not against the A549 lung cancer cell line or normal cells (MCF10A and WBC). Compound 4C caused MCF-7 cell death by apoptosis as visualized by fragmented nuclei and smeared genomic DNA. Furthermore, compound 4C increased caspase 9 mRNA levels and caused its activation. Additionally, compound 4C-treated MCF-7 cells showed enhanced cytochrome -c- release from a mitochondria to the cytosol, reflecting the initiation of the intrinsic apoptotic pathway. Finally, compound 4C exhibited EGFR kinase inhibitory activity (7.15 µM) which was supported by the molecular docking studies that showed compound 4C might be considered as a potential inhibitor of EGFR kinase.

Human and murine steroid 5β-reductases (AKR1D1 and AKR1D4): insights into the role of the catalytic glutamic acid

Mammalian steroid 5β-reductases belong to the Aldo-Keto Reductase 1D sub-family and are essential for the formation of A-ring 5β-reduced steroids. Steroid 5β-reduction is required for the biosynthesis of bile-acids and the metabolism of all steroid hormones that contain a Δ4-3-ketosteroid functionally to yield the 5β-reduced metabolites. In mammalian AKR1D enzymes the conserved catalytic tetrad found in all AKRs (Y55, H117, K84 and D50) has changed in that the conserved H117 is replaced with a glutamic acid (E120). E120 may act as a “superacid” to facilitate enolization of the Δ4-ketosteroid. In addition, the absence of the bulky imidazole side chain of histidine in E120 permits the steroid to penetrate deeper into the active site so that hydride transfer can occur to the steroid C5 position. In murine steroid 5β-reductase AKR1D4, we find that there is a long-form, with an 18 amino-acid extension at the N-terminus (AKR1D4L) and a short-form (AKR1D4S), where the latter is recognized as AKR1D4 by the major data-bases. Both enzymes were purified to homogeneity and product profiling was performed. With progesterone and cortisol, AKR1D4L and AKR1D4S catalyzed smooth conversion to the 5β-dihydrosteroids. However, with Δ4-androstene-3,17-dione as substrate, a mixture of products was observed which included, 5β-androstane-3,17-dione (expected) but 3α-hydroxy-5β- androstan-17-one was also formed. The latter compound was distinguished from its isomeric 3β-hydroxy-5β-androstan-17-one by forming picolinic acid derivatives followed by LC-MS. These data show that AKR1D4L and AKR1D4S also act as 3α-hydroxysteroid dehydrogenases when presented with Δ4-androstene-3,17-dione and suggest that E120 alters the position the steroid to enable a correct trajectory for hydride transfer and may not act as a “superacid”.

Synthesis and optoelectronic properties of dinuclear iridium (III) complexes containing deep blue fluorescence chromophore in the single-emissive-layer WPLEDs

To explore the influence of molecular structure on formation excimer and obtain high efficiency white polymer light-emitting devices (WPLEDs), two novel blue-emitting dinuclear cyclometalated iridium (III) complexes, namely C8DBCzC6-DF2Ir(pic) and DPy(TPA)-C6DBCzC6-DF2Ir(pic), have been successfully synthesized and characterized, in which DBCz is 3,6-diphenyl-carbazole bridged core, DPy(TPA) is 4,4′-di(pyren-1-yl)triphenylamine deep blue-emitting fluorescent chromophore, DF2Ir(pic) is dinuclear iridium (III) bis[(4,6-difluorophenyl)-pyridinato-N,C2′](picolinate) blue-emitting phosphorescent chromophore, and C6 is an nonconjugated dioxyhexyloxy linkage, respectively, and each parts of molecular skeleton are wired through nonconjugated ether linkage. Their thermal, electrochemical and optophysical properties were primarily investigated. Near white light emission were obtained in the C8DBCzC6-DF2Ir(pic)-doped devices using a blend of polyvinylcarbazole (PVK) and 2-(4-biphenyl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole (PBD) as a host matrix at dopant concentrations of 1 wt%. However, after triphenylamine functionalized pyrene DPy(TPA) replaced the alkyl chain C6 unit, at first unexpected, substitution effect occurs, more stable white light emissions with the CIE coordinates of (0.297 ± 0.009, 0.345 ± 0.007) and a maximum brightness of 961 cd/m2 were observed in the same device at the doping concentrations of 8 wt% under different applied voltages from 8 to 13 V. The results indicate that aggregation/excimer emissions of iridium (III) complexes can be effectively tuned by inserting a deep blue fluorescent chromophore into the dual picolinic acid derivative, and it aslo be an efficient way to get white-emitting WPLEDs.

Fragment screening ofN-acetylmannosamine kinase reveals noncarbohydrate inhibitors

Many biological processes from infection to tumor immune evasion are controlled by cell surface sialylation. To gather further insight into these processes, methods to alter cell surface sialylation are required. One way to achieve this is inhibiting the key enzyme of sialic acid de novo biosynthesis, the intracellular bifunctional UDP-N-acetylglucosamine epimerase/N-acetylmannosamine kinase (GNE/MNK). Here, we present low molecular weight inhibitors of MNK activity based on picolinic acid derivatives. They were identified in a fragment screening using19F NMR and validated in a biochemical inhibition assay followed by a structure–activity relationship analysis and docking. The optimized compound 6-carbamoylpicolinic acid inhibits MNK with a double-digit micromolar affinity. Its low molecular weight (166 Da) renders this picolinic acid derivative an exquisite starting point for the development of high-affinity MNK inhibitors, which may serve as molecular probes or lead candidates in future.

Transformation of Streptonigrin to Streptonigrone: Flavin Reductase-Mediated Flavin-Catalyzed Concomitant Oxidative Decarboxylation of Picolinic Acid Derivatives

In the flavin-reductase-catalyzed reducing condition, a mild and efficient α-hydroxylation and decarboxylation procedure using natural flavins as a catalyst and atmospheric oxygen as an external oxidizing agent has been successfully developed and applied to the synthesis of streptonigrone from streptonigrin. This reaction was achieved not only with streptonigrin analogues but also with structurally diverse electron-rich picolinic acid derivatives. The hydroxylation and decarboxylation may take place in a concerted manner.

含载流子基团的蓝色磷光铱配合物的合成及发光性能研究

Based on conventional high-efficiency blue-emitting di[2-(2,4-diflurophenyl) pyridine-N,C2](piconilic acid) iridium(III) (FIrPic), novel iridium complexes FIr(G-Pic) with donor (D)-acceptor (A) and A-D-A structures were synthesized and characterized by 1H NMR, 13C NMR and element analysis, in which G-pic is picolinic acid derivative containing carrier-transporting groups by a non-conjugated connection of 1,6-dioxyhexane. Moreover, their thermal properties, electrochemical properties and photophysical properties were investigated. These iridium complexes displayed an identical blue emission peak at 472 nm. The results show that there is little influence on the photoluminescent spectra of the iridium complexes as the carrier groups were introducted into the ligand of FIrPic by non-conjugated connection. In contrast, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy levels were elevated about 0.1 eV. This indicates that much more effects were taken into the electrochemical properties of these iridium complexes. At the same time, the thermal stabilities of these iridium complexes were also improved, and their onset degradation temperatures ( T d) for 5% weight loss are higher than 250 °C.

Synthesis and optoelectronic properties of a novel dinuclear cyclometalated platinum(II) complex containing triphenylamine-substituted indolo[3,2-b]carbazole derivative in the single-emissive-layer WPLEDs

A novel bi-picolinic acid derivative of H2dipic-BTICz containing binary triphenylamine-substituted indolo[3,2-b]carbazole (BTICz) unit and its dinuclear platinum(II) complex of (dfppy)2Pt2(dipic-BTICz) were synthesized as a single-component emitter used in the white polymer light-emitting diodes (WPLEDs), where dfppy is 2-(2,4-difluorophenyl)pyridine and dipic-BTICz is an anion of H2dipic-BTICz. The photophysical and electrochemical properties of (dfppy)2Pt2(dipic-BTICz) were investigated. Compared with the reported mononuclear platinum complex of (dfppy)Pt(pic), (dfppy)2Pt2(dipic-BTICz) exhibited a red-shifted photoluminescent peak at 434 nm in dilute dichloromethane (10−5 M), but a weakened and red-shifted aggregation emission peak at 640 nm besides its intrinsic emission at 445 nm in its neat films. Stable pure white emissions with CIE coordinates of (0.325±0.005, 0.345±0.015) and a maximum brightness of 208 cd/m2 were observed in the (dfppy)2Pt2(dipic-BTICz)-doped single-emissive-layer (SEL) PLEDs using a blend of poly(vinylcarbazole) and 2-(4-biphenyl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole as a host matrix at 1 wt % dopant concentrations under applied voltages from 9 to 14 V. It indicates that the intrinsic and aggregation emissions of this dinuclear platinum complex were effectively tuned by inserting a new BTICz fluorophore in the dual picolinic acid derivative. Therefore, it is a promising single-component emitter to get white emission in SEL PLEDs.

Penicolinates A–E from endophytic Penicillium sp. BCC16054

Five new picolinic acid derivatives, penicolinates A–E (1–5), together with four known compounds including phenopyrrozin (6), p-hydroxyphenopyrrozin (7), gliotoxin (8), and bisdethiobis(methylthio)gliotoxin (9) were isolated from endophytic Penicillium sp. BCC16054. The chemical structures were established from spectroscopic data-1D and 2D NMR experiments, IR, UV, and HRESIMS. These compounds were evaluated for antimalarial and antitubercular activities and for their activity against Bacillus cereus and Candida albicans along with cytotoxicity against both cancerous and non-cancerous cells.

Pyridomycin: Evaluating its antimycobacterial potential through the synthesis and testing of new analogues

Pyridomycin is an antimycobacterial depsipeptide produced by Streptomyces pyridomyceticus. Its constitution and absolute configuration were determined by X-ray crystallography. Pyridomycin is a twelve-membered ring with a semicyclic (Z)-s-butylidene group, 3-pyridylmethyl and hydroxypicolinoyl side chains and five stereocentres. It shows activity against Mycobacterium tuberculosis at 2–5µg/ml and some Gram-negative bacteria. The poster will present the successful establishment of the synthesis of various twelve-membered ring derivatives related to pyridomycin. After assembling the peptide building blocks, the ring closure poses the crucial point of the whole synthetic procedure (possible polymerization, difficult work up etc). With regard to the difficult isolation, we found that direct substitution with the picolinic acid derivatives represented a viable alternative (Fig.1). We report the first microbial evaluation using different mycobacterial species as well as Gram-negative and Gram-positive bacteria. In addition we determined the antiproliferative and cytotoxic effects of the new substances.

ChemInform Abstract: Enantioselective Synthesis of Pyrrolidine‐, Piperidine‐, and Azepane‐Type N‐Heterocycles with α‐Alkenyl Substitution: The CpRu‐Catalyzed Dehydrative Intramolecular N‐Allylation Approach.

A cationic CpRu complex of chiral picolinic acid derivatives [(R)- or (S)-Cl-Naph-PyCOOCH2CH═CH2] catalyzes asymmetric intramolecular dehydrative N-allylation of N-substituted ω-amino- and -aminocarbonyl allylic alcohols with a substrate/catalyst ratio of up to 2000 to give α-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1. The wide range of applicable N-substitutions, including Boc, Cbz, Ac, Bz, acryloyl, crotonoyl, formyl, and Ts, significantly facilitates further manipulation toward natural product synthesis.

Enantioselective Synthesis of Pyrrolidine-, Piperidine-, and Azepane-Type N-Heterocycles with α-Alkenyl Substitution: The CpRu-Catalyzed Dehydrative Intramolecular N-Allylation Approach

A cationic CpRu complex of chiral picolinic acid derivatives [(R)- or (S)-Cl-Naph-PyCOOCH(2)CH═CH(2)] catalyzes asymmetric intramolecular dehydrative N-allylation of N-substituted ω-amino- and -aminocarbonyl allylic alcohols with a substrate/catalyst ratio of up to 2000 to give α-alkenyl pyrrolidine-, piperidine-, and azepane-type N-heterocycles with an enantiomer ratio of up to >99:1. The wide range of applicable N-substitutions, including Boc, Cbz, Ac, Bz, acryloyl, crotonoyl, formyl, and Ts, significantly facilitates further manipulation toward natural product synthesis.

Elegant Approach to the Synthesis of a Unique Heteroleptic Cyclometalated Iridium(III)-Polyoxometalate Conjugate

A novel heteroleptic cyclometalated iridium(III) complex with one picolinic acid derivative bearing a pendant terminal alkynyl tether has been prepared following a new synthetic route. This pendant alkynyl tether can be further engaged in palladium C–C coupling reactions, allowing its grafting to a Keggin-type polyoxometalate and thus providing a unique iridio-POM conjugate.

6-Phosphoryl Picolinic Acids as Europium and Terbium Sensitizers

Three 6-phosphoryl picolinic acid (6PPA) derivatives were synthesized and used as europium and terbium sensitizers. Two of the three ligands (6-diethoxyphosphoryl picolinic acid (Hdeppa) and 6-monoethoxyphosphoryl picolinic acid (H(2)meppa)) are water-soluble, once complexed to lanthanide ions, while the third (6-dihydroxyphosphoryl picolinic acid (H(3)dhppa)) forms a precipitate. The stability constants of the phosphoryl-based complexes were found to be higher than the carboxylate analogue (dipicolinic acid, H(2)dpa). The main species are the [LnL(3)] complexes under strict stoichiometric conditions, confirmed by (31)P NMR spectroscopy, mass spectrometry and lifetime analyses. The photophysical measurements reveal that the emission intensity of [Eu(deppa)(3)] is maximal at pH 4.8, whereas for [Eu(meppa)(3)](3-), the optimum pH is observed at 9.0. The lifetimes are all in the millisecond range and have confirmed the absence of water molecules in the first coordination sphere. The emissions of the terbium are always brighter than the corresponding europium within this phosphoryl series. The quantum yields of the phosphoryl containing complexes are lower than the carboxylate analogue ([Ln(dpa)(3)](3-)), except for [Tb(deppa)(3)], which exhibits an interesting quantum yield of 40% in aqueous solution.

Single-layer white polymer light-emitting diodes based on an iridium (III) complex containing alkyltrifluorene picolinic acid

To explore the relationship between the electronic properties of a host/dopant system and obtain a high-efficiency single-dopant white polymer light-emitting device two novel blue-emitting cyclometalated iridium (III) complexes of (dfppy) 2Ir(Tfl-pic) and (dfppy) 2Ir(Brfl-pic) have been synthesized and characterized, where dfppy is 2-(2,4-difluorophenyl)pyridine, Tfl-pic and Brfl-pic are picolinic acid derivatives containing trialkylfluorene and dibromoalkylfluorene units bridged with an alkoxy chain, respectively. Both iridium (III) complexes exhibited blue emission in dichloromethane solution and their neat films, and possessed good dispersibility and thermal properties. Two different devices using (dfppy) 2Ir(Tfl-pic) as a single component emitter and a blend of poly( N-vinylcarbazole) and 2-(4-biphenyl)-5-(4- tert-butylphenyl)-1,3,4-oxadiazole as the host matrix were fabricated. Improved white emission was obtained by adjusting the electron injection layer leading to efficient exciplex emission.