RESUMO
A series of bile acid-polyamine amides conjugated with 3'-azido-3'-deoxythymidine (AZT) as potential antitumor prodrugs in the form of phosphoramidates were synthesized in good yields and their antitumor activities were assayed against two human cancer cells in vitro: cervix cancer HeLa cells and renal cancer 7860 cells. The improved antitumor activity probably derived from the enhanced delivery efficiency of AZT due to bile acid-polyamine conjugates.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Ácidos e Sais Biliares/química , Poliaminas/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Zidovudina/farmacologia , Amidas/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Células HeLa , Humanos , Nucleosídeos/química , Ácidos Fosfóricos/química , Pró-Fármacos/síntese química , Zidovudina/químicaRESUMO
2-,3-,4-Pyridylphosphonates and their phosphonothioate congeners were analyzed by electrospray ionization multistage tandem mass spectrometry (ESI-MS(n)). It was found that the fragmentation pathways of these compounds were not influenced to any detectable extent by the stereochemistry at the phosphorus centers but were sensitive to the position of a nitrogen atom in the pyridine ring of these compounds. Possible mechanisms for fragmentations of the investigated compounds are discussed in detail.
Assuntos
Nitrogênio/química , Nucleosídeos/química , Compostos Organofosforados/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Dimerização , Conformação Molecular , Sensibilidade e Especificidade , EstereoisomerismoRESUMO
Molecular dynamics simulations were performed on modeled kinase-substrate complexes in an attempt to establish a relationship between structural features and binding ability of the complexes. We found that the monitored distance between substrate nucleophilic oxygen (OG) and attacked phosphorus (PG) of ATP analog correlated closely with the binding affinity. With reference to 3.3 A, the van der Waals sum of oxygen and phosphorus, the calculated distances of good substrates were close to it whereas those of poor substrates were far apart from it. Therefore, it is reasonable to consider the OG-PG distance as a potential criterion to prefigure the kinase-substrate binding specificity and the simple computational techniques may work as an easy approach to distinguish good substrates from weak or poor substrates.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Domínio Catalítico , Simulação por Computador , Bases de Dados de Proteínas , Técnicas In Vitro , Cinética , Modelos Moleculares , Oxigênio/química , Peptídeos/química , Peptídeos/metabolismo , Fósforo/química , Fosforilase Quinase/química , Fosforilase Quinase/metabolismo , Especificidade por Substrato , TermodinâmicaRESUMO
Molecular interaction between seryl-histidine (or seryl-histidine related dipeptides) and DNA model molecule 5'-TpTpdC-3' was studied by a molecular docking procedure. The key structural features of DNA cleaving activity were investigated.
