József Kaizer

Kinetics and mechanism of the Cu(I) and Cu(II) flavonolate-catalyzed oxygenation of flavonol. Functional quercetin 2,3-dioxygenase models

Abstract The oxygenation of flavonol (flaH) using Cu II (fla) 2 and Cu I (fla)(PPh 3 ) 2 catalysts results in oxidative cleavage of the heterocyclic ring to give O -benzoylsalicylic acid ( O -bsH) and CO as primary products. The oxygenolysis of flavonol catalyzed by Cu II (fla) 2 in DMF was followed by electronic spectroscopy and the rate law was found to be −d[flaH]/d t = k obs [flaH][Cu II (fla) 2 ][O 2 ]. The rate constant, activation energy, activation enthalpy and entropy at 393 K are as follows: k obs /s −1 mol −2 dm −6 =(2.02±0.07)×10 3 , E a /kJ mol −1 =142±6, Δ H ‡ /kJ mol −1 =139±5, and Δ S ‡ /J mol −1 K −1 =168±13. The results of the kinetic measurements of the Cu I (fla)(PPh 3 ) 2 -catalyzed oxygenation shows that in the presence of a large excess of the substrate, the Cu I (fla)(PPh 3 ) 2 reacts with flavonol in an irreversible step to Cu II (fla) 2 , and, then, the mechanism of the oxygenation is the same as that with the Cu II (fla) 2 -catalyzed reaction.

Synthesis and characterization of copper(I) and copper(II) flavonolate complexes with phthalazine ligand, and their oxygenation and relevance to quercetinase

Abstract Copper(I) and copper(II) flavonolate (fla) complexes with 1,4-(di-2′-pyridyl)aminophthalazine ligand (PAPH 2 ) have been prepared by the reaction of copper salts with flavonol and the ligand in acetonitrile or dichloromethane. The copper(II) centers are bound to the tetradentate phthalazine ligand resulting in both mononuclear and binuclear complexes. Flavonol is oxygenated to the corresponding depside catalyzed by flavonolato copper(II) phthalazine complexes.

One metal–two pathways to the carboxylate-enhanced, iron-containing quercetinase mimics

Mononuclear iron(iii) flavonolate was synthesized as synthetic enzyme-substrate complex, and its direct and carboxylate-enhanced dioxygenation as biomimetic functional models with relevance to flavonol 2,4-dioxygenase are briefly described.

1-Aminocyclopropane-1-carboxylic acid oxidase: insight into cofactor binding from experimental and theoretical studies

Abstract1-Aminocyclopropane-1-carboxylic acid oxidase (ACCO) is a nonheme Fe(II)-containing enzyme that is related to the 2-oxoglutarate-dependent dioxygenase family. The binding of substrates/cofactors to tomato ACCO was investigated through kinetics, tryptophan fluorescence quenching, and modeling studies. α-Aminophosphonate analogs of the substrate (1-aminocyclopropane-1-carboxylic acid, ACC), 1-aminocyclopropane-1-phosphonic acid (ACP) and (1-amino-1-methyl)ethylphosphonic acid (AMEP), were found to be competitive inhibitors versus both ACC and bicarbonate (HCO3−) ions. The measured dissociation constants for Fe(II) and ACC clearly indicate that bicarbonate ions improve both Fe(II) and ACC binding, strongly suggesting a stabilization role for this cofactor. A structural model of tomato ACCO was constructed and used for docking experiments, providing a model of possible interactions of ACC, HCO3−, and ascorbate at the active site. In this model, the ACC and bicarbonate binding sites are located close together in the active pocket. HCO3− is found at hydrogen-bond distance from ACC and interacts (hydrogen bonds or electrostatic interactions) with residues K158, R244, Y162, S246, and R300 of the enzyme. The position of ascorbate is also predicted away from ACC. Individually docked at the active site, the inhibitors ACP and AMEP were found coordinating the metal ion in place of ACC with the phosphonate groups interacting with K158 and R300, thus interlocking with both ACC and bicarbonate binding sites. In conclusion, HCO3− and ACC together occupy positions similar to the position of 2-oxoglutarate in related enzymes, and through a hydrogen bond HCO3− likely plays a major role in the stabilization of the substrate in the active pocket.

Radical-initiated oxygenation of flavonols by dioxygen

Abstract In the presence of free radicals, such as 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) and 2,6-di-tert-butyl-a-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene)-p-tolyloxyl (galvinoxyl), flavonols undergo catalytic oxygenation to the corresponding depsides (phenolic carboxylic acid esters), with concomitant evolution of CO. The oxygenolysis was performed in aprotic solvents (DMF, MeCN) and was followed by Glc. The results of oxygenation of 4′-substituted flavonols show that the formation of flavonoxy species is the key step in the activation process of the substrate, and that electron-releasing substituents enhance the reaction rate.

Isoindoline-derived ligands and applications

During the past decade isoindoline-based ligands became the subject of growing interest due to their modular set-up. In this review the structure and reactivity of these ligands and their transition metal complexes are covered. Beyond the discussion of the structural properties particular attention is paid to the expanding fields of applications of these compounds.

Copper-mediated oxygenation of flavonolate in the presence of a tridentate N-ligand. Synthesis and crystal structures of [Cu(fla)(idpaH)]ClO4 and [Cu(idpaH)(O-bs)]ClO4, [fla = flavonolate, idpaH = 3,3'-iminobis(N,N-dimethylpropylamine), O-bs = O-benzoylsalicylate]

Abstract The complexes [Cu(fla)(idpaH)]ClO4 (4) and [Cu(idpaH)(O-bs)]ClO4 (5) (fla=flavonolate, idpaH=3,3′-iminobis(N,N-dimethylpropylamine), O-bs=O-benzoylsalicylate) have been synthesised and characterised. Complex 5 can be obtained also by the oxygenation of 4 and concomitant CO release. The structures of the compounds have been determined by X-ray diffraction. Complex 4 exhibits distorted trigonal-bipyramidal geometry around the copper(II) ion while complex 5 is distorted square-pyramidal.

Bio-inspired flavonol and quinolone dioxygenation by a non-heme iron catalyst modeling the action of flavonol and 3-hydroxy-4(1H)-quinolone 2,4-dioxygenases

The mononuclear complex, Fe(III)(O-bs)(salen) (salenH(2)=1,6-bis(2-hydroxyphenyl)-2,5-diaza-hexa-1,5-diene; O-bsH=O-benzoylsalicylic acid) was synthesized as synthetic enzyme-depside complex, and characterized by spectroscopic methods and X-ray crystal analysis. The dioxygenation of flavonol (flaH) and 3-hydroxy-4-quinolone (quinH(2)) derivatives in the presence of catalytic amounts of Fe(III)(O-bs)(salen) results in the oxidative cleavage of the heterocyclic ring to give the corresponding O-benzoylsalicylic and anthranilic acid derivatives with concomitant release of carbon monoxide. These reactions can be regarded as biomimetic functional models with relevance to the iron-containing flavonol and the cofactor-independent 3-hydroxy-4(1H)-quinolone 2,4-dioxygenases.

Carboxylate-enhanced reactivity in the oxygenation of copper flavonolate complexes

The oxygenolytic cleavage of flavonolate coordinated to copper(II) with the auxiliary ligand 3,3′-iminobis(N,N-dimethylpropylamine), [CuII(fla)(idpa)]ClO4, is enhanced by the addition of acetate and benzoate. Monodentate coordination of the flavonolate forced by the carboxylate ligands is believed to be the reason for the higher reaction rates.

Formation, Characterization, and Reactivity of a Nonheme Oxoiron(IV) Complex Derived from the Chiral Pentadentate Ligand asN4Py

The chiral pentadentate low-spin (S = 1) oxoiron(IV) complex [FeIV(O)(asN4Py)]2+ (2) was synthesized and spectroscopically characterized. Its formation kinetics, reactivity, and (enantio)selectivity in an oxygen-atom-transfer reaction was investigated in detail and compared to a similar pentadentate ligand-containing system.