1,721,003 research outputs found
Inhibitory activity of flavonols toward the xanthine oxidase enzyme
No full textThe spectrophotometric methods of analysis adopted for the study of the inhibition of the enzyme, xanthine oxidase, are very different as regards the time required for the assay. With a view to studying the inhibitory effect of flavonoids, we examined the stability and the inhibitory activity of quercetin and myricetin in relation to environment and time. The results show that, in a buffer solution of pH 7.6 at 20-degrees-C, these flavonols undergo transformation in accordance with the environment and that their transformation products have a lower inhibitory capacity towards xanthine oxidase. The method that assesses the initial rate of formation of uric acid is therefore that which affords the most reliable results regarding the activity of flavonols; accordingly, this was the method used to determine the kinetic parameters of the enzymatic inhibition exerted by quercetin and myricetin
A model of the interaction of substrates and inhibitors with xanthine oxidase
No full textA model of the interaction of substrates and inhibitors with xanthine oxidase (XO) based on similarity concepts and molecular modeling is introduced and discussed, and previous literature is reexamined in the light of recent insights into the mechanism and structure of XO. Use is made of quantum-chemical calculations with the inclusion of solvent effects, molecular superimposition with least-squares fitting algorithms, and molecular electrostatic potentials. First, the relative stabilities of the tautomeric forms of the physiological substrates, xanthine and hypoxanthine, are calculated both in vacuo and in water in order to select the most abundant form(s) at physiological pH: the two substrates prove to be stable in their lactam forms, with a dominance of the N-7-H tautomer for xanthine and of N-9-H for hypoxanthine. The structures of xanthine and hypoxanthine are then superimposed, and their relative orientation with respect to the molybdenum center of XO is suggested. The criteria used for superimposition reflect the importance of functional groups of xanthine and hypoxanthine, as inferred from experimental work. In particular, the carbonyl oxygen common to the two substrates is given special consideration on account of its determinant role. The results show that the most important functional groups of the two substrates can be successfully superimposed by means of a rotation that exchanges the five-membered with the six-membered rings of xanthine and hypoxanthine with respect to molybdenum. The close similarity of the electrostatic potentials of the two superimposed molecules adds weight to the proposed orientation of the substrates in the binding site. The model of interaction is then tested and further developed using a series of previously-synthesized dimensional analogs of xanthine and hypoxanthine. The results confirm that the correct positioning of the carbonyl group is essential if a productive interaction with XO is to be achieved and allow us to map the dimensions of the active site starting from the superimposition of the physiological substrates. Two hypotheses regarding the amino acid residues interacting with the important carbonyl oxygen of the substrates are then put forward on the basis of spectroscopic and biochemical evidence: they are postulated to be one lysine or one protonated glutamic acid residue. In an attempt to unify the binding of substrates and inhibitors, the model is extended to the inhibitors of XO by superimposing the most interesting inhibitors developed by Robins on xanthine and hypoxanthine. This allows us to define the most suitable location of the phenyl rings of these inhibitors with respect to the superimposition of the substrates. Intriguingly, the superimpositions of the most active inhibitors are consistent with a unique location of their phenyl rings, even though they are in different positions on the purine ring. Finally, the flavone, which is a potent inhibitor of XO and is currently under investigation by the authors, is accounted for by these findings and successfully included in the model. This model incorporates many important insights into XO and can be of general interest. Moreover, it represents a clear-cut alternative to a previous model developed by Robins on the basis of the coordination of substrates and inhibitors to molybdenum
ANTHOCYANIDINES AS INHIBITORS OF XANTHINE-OXIDASE
No full textAnthocyanidines as inhibitors of xanthine oxidas
A rational approach to the design of flavones as xanthine oxidase inhibitors
No full textIn the light of previous QSAR studies on flavones as inhibitors of xanthine oxidase, we synthesized and tested a new series of 7-hydroxyflavones carrying a wide and balanced variety of substituents (pi, sigma(p)) at the 4' position in order to explore the effect of substituents at this position on the xanthine oxidase inhibitory activity. The results of pK(a) determinations show that the electronic effects of the substituents are not transferred to the hydroxyl at C7, previously found to be fundamental for activity. An excellent correlation is found between molar refractivity of the substituents and the inhibitory activity. These results, applied to the more active 5,7-dihydroxyflavones, allowed the design and synthesis of a very active inhibitor, with an IC50 in the nanomolar range. On interpretative grounds, C4' substituents of flavones are involved in dispersion interactions with the enzyme. The calculation of quantum chemical polarizabilities and solvent accessible surface areas suggests the existence of pi-pi stacking interactions with an aromatic aminoacidic residue of the enzyme
Physico-chemical properties of anthocyanidins. Part 1. Theoretical evaluation of the stability of the neutral and anionic tautomeric forms
No full textQuantum chemical (AM1) and solvation model calculations have been applied to the study of tautomeric stabilities in three anthocyanidins, so as to single out the dominant tautomeric forms (neutral and anionic) at physiological pH. The theoretical information concerning the tautomeric stabilities and electronic structures of anthocyanidins are essential for the development of quantitative structure-activity relationships. The present results allow us to discriminate between the wide variety of tautomeric forms, and to infer that, depending on the pH, only two neutral tautomers and two anionic tautomers should be present in solution. On interpretative grounds, the main factors determining stability are chiefly ascribable to the extent of pi-electron delocalization and to the possibility of classical resonance structures. Several theoretical descriptors have been calculated for use in quantitative structure-activity relationships
Chromium Toxicity in Salvia sclarea - I. Effects of Hexavalent Chromium on Seed Germination and Seedling Development
No full textTheoretical and experimental study of flavones as inhibitors of xanthine oxidase
No full textInhibitory activities of 19 polyhydroxylated and polymethoxylated flavones towards xanthine oxidase have been obtained by accurate measurements of the dissociation constants of enzyme-inhibitor complexes (K-EI). A topological description of the congeneric series has been adopted to derive quantitative structure-activity relationships (QSAR) with the use of multiple linear regression analysis. For interpretative purposes, molecular orbital calculations have also been performed. Inhibition appears to involve flavones as donors and the anion at the C-7 hydroxyl as the most active form in solution. Substituents in the 4H-1-benzopyran-4-one moiety can directly affect the availability of the C-7 anion in solution; substituents in the 2-phenyl moiety are probably involved in secondary local interactions with the enzyme
Caratteristiche degli olii essenziali di piante di Lavandula hybrida Reverchon “Grosso” coltivate in aree appenniniche
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