Chelidamic acid

Pseudopolymorphs of chelidamic acid and its dimethyl ester

Different tautomeric and zwitterionic forms of chelidamic acid (4-hydroxypyridine-2,6-dicarboxylic acid) are present in the crystal structures of chelidamic acid methanol monosolvate, C(7)H(5)NO(5)·CH(4)O, (Ia), dimethylammonium chelidamate (dimethylammonium 6-carboxy-4-hydroxypyridine-2-carboxylate), C(2)H(8)N(+)·C(7)H(4)NO(5)(-), (Ib), and chelidamic acid dimethyl sulfoxide monosolvate, C(7)H(5)NO(5)·C(2)H(6)OS, (Ic). While the zwitterionic pyridinium carboxylate in (Ia) can be explained from the pK(a) values, a (partially) deprotonated hydroxy group in the presence of a neutral carboxy group, as observed in (Ib) and (Ic), is unexpected. In (Ib), there are two formula units in the asymmetric unit with the chelidamic acid entities connected by a symmetric O-H···O hydrogen bond. Also, crystals of chelidamic acid dimethyl ester (dimethyl 4-hydroxypyridine-2,6-dicarboxylate) were obtained as a monohydrate, C(9)H(9)NO(5)·H(2)O, (IIa), and as a solvent-free modification, in which both ester molecules adopt the hydroxypyridine form. In (IIa), the solvent water molecule stabilizes the synperiplanar conformation of both carbonyl O atoms with respect to the pyridine N atom by two O-H···O hydrogen bonds, whereas an antiperiplanar arrangement is observed in the water-free structure. A database study and ab initio energy calculations help to compare the stabilities of the various ester conformations.

Synthesis, characterization, X-ray crystal structure, DFT calculation and antibacterial activities of new vanadium(IV, V) complexes containing chelidamic acid and novel thiourea derivatives

Three new thiourea ligands derived from the condensation of aroyl- and aryl-isothiocyanate derivatives with 2,6-diaminopyridine, named 1,1'-(pyridine-2,6-diyl)bis(3-(benzoyl)thiourea) (L1), 1,1'-(pyridine-2,6-diyl)bis(3-(2-chlorobenzoyl)thiourea) (L2) and 1,1'-(pyridine-2,6-diyl)bis(3-(4-chlorophenyl)thiourea) (L3), their oxido-vanadium(IV) complexes, namely [VO(L1('))(H2O)] (C1), [VO(L2('))(H2O)] (C2) and [VO(L3('))(H2O)] (C3), and also, dioxo-vanadium(V) complex containing 4-hydroxy-2,6-pyridine dicarboxylic acid (chelidamic acid, H2dipic-OH) and metformin (N,N-dimethylbiguanide, Met), named [H2Met][VO2(dipic-OH)]2·H2O (C4), were synthesized and characterized by elemental analysis, FTIR and (1)H NMR and UV-visible spectroscopies. Proposed structures for free thiourea ligands and their vanadium complexes were corroborated by applying geometry optimization and conformational analysis. Solid state structure of complex [H2Met][VO2(dipic-OH)]2·H2O (triclinic, Pī) was fully determined by single crystal X-ray diffraction analysis. In this complex, metformin is double protonated and acted as counter ion. The antibacterial properties of these compounds were investigated in vitro against standard Gram-positive and Gram-negative bacterial strains. The experiments showed that vanadium(IV) complexes had the superior antibacterial activities than novel thiourea derivatives and vanadium(V) complex against all Gram-positive and Gram-negative bacterial strains.

A nano-structured Ni(II)-chelidamic acid modified gold nanoparticle self-assembled electrode for electrocatalytic oxidation and determination of methanol

A nano-structured Ni(II)-chelidamic acid (2,6-dicarboxy-4-hydroxypyridine) film was electrodeposited on a gold nanoparticle-cysteine-gold electrode. The morphology of Ni(II)-chelidamic acid gold nanoparticle self-assembled electrode was investigated by scanning electron microscopy (SEM). Electrocatalytic oxidation of methanol on the surface of modified electrode was studied by cyclic voltammetry and chronoamperometry methods. The hydrodynamic amperometry at a rotating modified electrode at constant potential versus reference electrode was used for detection of methanol. Under optimized conditions the calibration plots are linear in the concentration range 0-50mM with a detection limit of 15μM. The formed matrix in our work possessed a 3D porous network structure with a large effective surface area, high catalytic activity and behaved like microelectrode ensembles. The modified electrode indicated reproducible behavior and a high level stability during the experiments, making it particularly suitable for analytical purposes.

Chelidonic acid and other conformationally restricted substrate analogues as inhibitors of rat brain glutamate decarboxylase

Twenty conformationally restricted analogues of glutamate including benzoic acids, hydroxy-benzoic acids, pyridine dicarboxylic acids, and pyran dicarboxylic acids were tested as inhibitors of glutamate decarboxylase from rat brain. Chelidonic acid, 2,6-pyridine dicarboxylic acid, chelidamic acid, gallic acid, and 3,4-dihydroxybenzoic acid were the most potent inhibitors of the enzyme, and generally the aromatic analogues were much more potent inhibitors than their aliphatic counterparts. An intercarboxylate distance of 0.75 nm appears optimal for substrate competition, indicating that glutamate binds to the active site in an extended conformation. At least one carboxyl group can be replaced by a phenolic hydroxyl without greatly affecting inhibition. The degree of inhibition was also influenced by the aromatic structure, particularly with respect to the atom bridging the dicarboxylate carbons. Kinetic analysis of the inhibition by chelidonic acid and chelidamic acid showed that these compounds were competitive with glutamate with Ki values of 1.2 and 33 microM respectively. Consistent with this result, chelidonic acid also inhibited the glutamate-dependent formation of apoenzyme. Chelidonic acid itself did not promote formation of apoenzyme and did not react with free pyridoxal-P. The effects of different classes of glutamate decarboxylase inhibitors are discussed in relation to the formation of apoenzyme and its reactivation by pyridoxal-P. As one of the most potent inhibitors of glutamate decarboxylase known, chelidonic acid may be of value in studies of the regulation of gamma-aminobutyric acid synthesis.

Synthesis, DNA-cleaving properties and cytotoxicity of intercalating chelidamic acid derivatives

We have explored the potential antitumour activity of DNA-intercalating free radical generators based on compounds constructed from 9-anilinoacridine and chelidamic acid as an iron (II) binding centre. Here we describe their synthesis, DNA cleaving ability and activity against a panel of human tumour cell lines in culture. We also investigate their potential for use as DNA footprinting agents. Previous work has shown that the parent compound, FTP1, cleaves DNA in an essentially sequence neutral fashion and has modest cytotoxicity [Searcey, M., McClean, S., Madden, B. & Wakelin, L.P.G. (1997) Journal of the Chemical Society. Perkin Transactions, 2, 523]. Here we have equipped the acridine chromophore with an N,N-dimethylaminoethyl-4-carboxamide substituent, giving the threading agent FTP2, which confers selectivity for cleaving in GC-rich sequences, avoidance for binding to AT-tracts and 8-fold enhanced cytotoxicity compared with FTP1. Although this side chain bestows slow dissociation kinetics on DNA complexes of 9-anilinoacridines, it does not enhance the overall cutting efficiency of FTP2, implying that free-radical generation, DNA hydrogen abstraction and sugar fragmentation are fast compared with DNA-ligand complex lifetimes. FTP2 does not appear to be susceptible to resistance by the mdr phenotype in human ovarian carcinoma cells. We also report that FTP2 is an effective footprinting agent for GC-selective binding ligands and that it has some advantages over FTP1 in this regard.