RESUMO
A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compounds possessed a phosphonate group in an endo orientation. This was consistent with molecular modeling results that showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores Enzimáticos/síntese química , Nucleosídeos de Pirimidina/síntese química , Timidina Fosforilase/antagonistas & inibidores , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Relação Estrutura-AtividadeRESUMO
The peptide sequence YIGSR, a segment of the basement membrane matrix glycoprotein laminin, has been identified as a key component in tumor cell invasion. Guided by extensive NMR work and de novo design algorithms, a nonpeptide mimetic of this pentapeptide was identified as a lead candidate for synthesis. The target displays the key amino acid side chains from a novel tricyclic scaffold. The first synthesis of this unique scaffold is completed in 11 steps and 7% overall yield.