RESUMO
The application of phosphorodiamidate technology to pyrimidine and purine nucleosides with anticancer activity to potentially overcome the resistance mechanisms associated with parent nucleosides is reported. Sixteen symmetrical phosphorodiamidates were prepared from the natural amino acids l-alanine and glycine. All the compounds were evaluated for their cytotoxic activity against a wide panel of solid and leukaemic tumour cell lines. In addition, a carboxypeptidase Y assay was performed on a representative phosphorodiamidate in order to reveal the putative bioactivation pathway for the reported phosphorodiamidate-type prodrugs.
Assuntos
Antineoplásicos/farmacologia , Compostos Organofosforados/farmacologia , Pró-Fármacos/farmacologia , Nucleosídeos de Purina/farmacologia , Nucleosídeos de Pirimidina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Catepsina A/química , Linhagem Celular Tumoral , Ensaios Enzimáticos , Humanos , Camundongos , Estrutura Molecular , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Nucleosídeos de Purina/síntese química , Nucleosídeos de Purina/química , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/químicaRESUMO
The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression.