Inhibition of Neurotoxic Secretory Phospholipases A(2) Enzymatic, Edematogenic, and Myotoxic Activities by Harpalycin 2, an Isoflavone Isolated from Harpalyce brasiliana Benth

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Secretory phospholipases A(2) (sPLA(2)) exert proinflammatory actions through lipid mediators. These enzymes have been found to be elevated in many inflammatory disorders such as rheumatoid arthritis, sepsis, and atherosclerosis. The aim of this study was to evaluate the effect of harpalycin 2 (Har2), an isoflavone isolated from Harpalyce brasiliana Benth., in the enzymatic, edematogenic, and myotoxic activities of sPLA2 from Bothrops pirajai, Crotalus durissus terrificus, Apis mellifera, and Naja naja venoms. Har2 inhibits all sPLA(2) tested. PrTX-III (B. pirajai venom) was inhibited at about 58.7%, Cdt F15 (C. d. terrificus venom) at 78.8%, Apis (from bee venom) at 87.7%, and Naja (N. naja venom) at 88.1%. Edema induced by exogenous sPLA(2) administration performed in mice paws showed significant inhibition by Har2 at the initial step. In addition, Har2 also inhibited the myotoxic activity of these sPLA(2)s. In order to understand how Har2 interacts with these enzymes, docking calculations were made, indicating that the residues His48 and Asp49 in the active site of these enzymes interacted powerfully with Har2 through hydrogen bonds. These data pointed to a possible anti-inflammatory activity of Har2 through sPLA(2) inhibition.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FUNCAP (Fundacao Cearense de Apoio a Pesquisa)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

The use of the generator coordinate method for designing basis set. Application to oxo-diperoxo molybdenum complexes

The molecular and electronic structures of MoO(O(2))(2) (1), MoO(O(2))(2)(OPY) (2) and MOO(O(2))(2)(OPY)(H(2)O) (3) complexes were investigated at the Hartree-Fock and density functional method (B3LYP) calculation levels. The generator coordinate method (GCM) has been used to design basis sets that properly represent the electronic density on the Mo and O atoms for all electron calculations, while a variant of the GCM method has been employed to design a valence basis set for the Mo atom for the pseudopotential calculations. Compound 1 adopts a distorted tetragonal pyramid structure, where the four peroxo oxygen atoms are located in the same plane, which is perpendicular to the axis defined by the Mo and oxo oxygen atoms. An analysis based upon the geometrical and electronic parameters and the vibrational frequencies renders that 1 can be described as two peroxide fragments bonded to the MoO moiety. 2 and 3 complexes are bipyramidal pentagonal structures, with the OPy ligand occupying a quasi-equatorial position in the same plane as the two peroxo triangles while the H(2)O ligand is situated trans to the oxo group in 3. A comparison between theoretical and experimental results for the geometry and vibrational frequencies of 3 complex shows good agreement. The relationship between the reactivity of 1, 2 and 3 complexes and their coordination number has been established by analyzing the values of the vibrational frequencies, frontier molecular orbitals and the values of electron affinities. (C) 2002 Elsevier Science B.V. All rights reserved.58925126