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1.
J Inorg Biochem ; 208: 111089, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32442762

RESUMO

Three novel Zn(II) complexes, [ZnCl2(qz)2] (1), [ZnCl2(1,5-naph)]n (2) and [ZnCl2(4,7-phen)2] (3), where qz is quinazoline, 1,5-naph is 1,5-naphthyridine and 4,7-phen is 4,7-phenanthroline, were synthesized by the reactions of ZnCl2 and the corresponding N-heterocyclic ligand in 1:2 molar ratio in ethanol at ambient temperature. The characterization of these complexes was done by NMR, IR and UV-Vis spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction analysis. Complexes 1 and 3 are mononuclear species, in which Zn(II) ion is tetrahedrally coordinated by two nitrogen atoms belonging to two qz or 4,7-phen ligands, respectively, and by two chloride anions, while complex 2 is a 1D coordination polymer that contains 1,5-naph as bridging ligand between two metal ions. In agar disc-diffusion assay, complexes 1-3 manifested good inhibitory activity against two investigated Candida strains (C. albicans and C. parapsilosis), while not inducing toxic effects on the healthy human fibroblast cell line (MRC-5). This activity was not fungicidal, as revealed by the broth microdilution assay, however complex 3 showed the ability to modulate Candida hyphae formation, which is an important process during infection and showed significant synergistic effect with clinically used antifungal polyene nystatin.


Assuntos
Antifúngicos , Candida albicans/crescimento & desenvolvimento , Candida parapsilosis/crescimento & desenvolvimento , Complexos de Coordenação , Compostos Heterocíclicos , Nistatina , Zinco , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/agonistas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Sinergismo Farmacológico , Compostos Heterocíclicos/agonistas , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Nistatina/agonistas , Nistatina/química , Nistatina/farmacologia , Zinco/agonistas , Zinco/química , Zinco/farmacologia
2.
Exp Hematol ; 37(9): 1072-83, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19539688

RESUMO

OBJECTIVE: Glycosaminoglycans (GAG) are major components of bone marrow extracellular matrix because they have the property to interact with cells and growth factors in hematopoietic niches. In this study, we investigated the effect of two different chemically defined GAG mimetics on mobilization of hematopoietic stem and progenitor cells (HSPCs) in mice peripheral blood. MATERIALS AND METHODS: Mobilization was achieved by intraperitoneal injection of GAG mimetics. Mobilized cells were characterized phenotypically by reverse transcription polymerase chain reaction and fluorescence-activated cell sorting analysis and functionally by colony-forming cell, cobblestone area-forming cell and long-term culture-initiating cell assays in vitro. Radioprotection assays were performed to confirm the functionality of primitive hematopoietic cells in vivo. Involvement of stromal-derived factor-1 (SDF-1) and matrix metalloproteinase-9 (MMP-9) were investigated. RESULTS: GAG mimetics treatment induces hyperleukocytosis and mobilization of HSPC. They synergize with the effects of granulocyte colony-stimulating factor or AMD3100 on hematopoietic progenitors mobilization. Reconstitution of lethally irradiated recipient mice with peripheral blood mononuclear cells from GAG mimetic-treated donor mice improves engraftment and survival. BiAcore studies indicate that the mimetics interact directly with SDF-1. In addition, GAG mimetics-induced mobilization is associated with increased levels of pro- and active MMP-9 from bone marrow cells and increased level of SDF-1 in peripheral blood. Finally, mobilization is partially inhibited by co-injection with anti-SDF-1 antibody. CONCLUSION: This study demonstrates that GAG mimetics induce efficient mobilization of HSPCs, associated with an activation of pro-MMP-9 and a modification in the SDF-1 concentration gradient between bone marrow and peripheral blood. We suggest that structural features of GAGs can modify the nature of mobilized cells.


Assuntos
Materiais Biomiméticos/farmacologia , Quimiocina CXCL12/sangue , Glicosaminoglicanos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Metaloproteinase 9 da Matriz/sangue , Animais , Fármacos Anti-HIV/agonistas , Fármacos Anti-HIV/farmacologia , Benzilaminas , Medula Óssea/metabolismo , Ciclamos , Sinergismo Farmacológico , Glicosaminoglicanos/agonistas , Sobrevivência de Enxerto/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/agonistas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/agonistas , Compostos Heterocíclicos/farmacologia , Masculino , Camundongos , Relação Estrutura-Atividade , Transplante Homólogo
3.
Br J Haematol ; 134(3): 326-9, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16787495

RESUMO

The CXCR4 antagonist, AMD3100, stimulates a rapid increase in circulating numbers of haematopoeitic progenitor cells (HPCs) in both mice and human healthy volunteers. An in situ perfusion system of the mouse femoral bone marrow was used to provide the first direct evidence that AMD3100 mobilises HPCs from the bone marrow. Structural analogues of AMD3100 demonstrated that the ability of these compounds to mobilise HPCs in vivo correlated with their capacity to antagonise CXCR4 in vitro. This model system was also used to demonstrate additive effects of AMD3100 administered acutely, with granulocyte colony-stimulating factor administered chronically, with respect to HPC mobilisation.


Assuntos
Quimiocinas CXC/metabolismo , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Receptores CXCR4/metabolismo , Animais , Benzilaminas , Células da Medula Óssea , Células Cultivadas , Quimiocina CXCL12 , Ciclamos , Depressão Química , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Compostos Heterocíclicos/agonistas , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Ligação Proteica/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores
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