RESUMO
Thermal ring transformation ability of unsaturated N-bridgehead fused pyrimidin-4(3H)-ones A is governed by both the steric and the electrostatic interactions between the oxygen of the carbonyl group and the substituent in the peri position.
Assuntos
Cicloparafinas/química , Compostos Heterocíclicos com 2 Anéis/química , Pirimidinonas/química , Ciclização , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.
Assuntos
Pirrolidinas/farmacologia , Serina Endopeptidases/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Sítios de Ligação/efeitos dos fármacos , Simulação por Computador , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ligação de Hidrogênio , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Prolil Oligopeptidases , Pirrolidinas/síntese química , Pirrolidinas/química , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The antibiotic fumagillin with amebicidal and fungicidal effects isolated from Aspergillus fumigatus is the only presently known agent for the treatment of life threatening serious microsporidiosis occurring in patients with AIDS. Fumagillin and its degradation products were measured by HPLC at given time intervals after storage under defined conditions (temperature, relative humidity). Significant degradation took place even in samples stored in freezer; therefore fumagillin drug substance should be stored below -60 degrees C. Light also induced a degradation process in fumagillin, thus it is proposed to be stored and transported in brown glass.
