RESUMO
The aim of the present work is to investigate through molecular modelling the possible role of the human enzyme Hint1 in the final P-N bond cleavage of phosphoramidate ProTides, which would lead to the intracellular delivery of unmasked nucleoside analogue monophosphates. Herein, we report our preliminary analysis based on docking studies of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) related aminoacyl phosphates with Hint1 and the effect of the amino acid moiety on the enzyme-substrate binding affinity.
Assuntos
Amidas/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Ácidos Fosfóricos/metabolismo , Bromodesoxiuridina/análogos & derivados , Bromodesoxiuridina/química , Bromodesoxiuridina/metabolismo , Domínio Catalítico , Humanos , Modelos Moleculares , Conformação Proteica , Especificidade por SubstratoRESUMO
The phosphoramidate technology we have developed has been recently applied to BVdU, leading to NB1011 (NewBiotics Inc., California), a novel potential anticancer compound recently entered into phase 2 of the clinical trials for colon cancer. We report in this work a new series of derivatives containing naphthol as aryl masking group on the phosphate moiety, which has shown a significant increase in anticancer activity in preliminary biological evaluations.