RESUMEN
We prepared a 5-fluorodeoxyuridine (5-FdUrd) derivative possessing azide methyl group (N(3)-FdUrd) as a novel radiation-activated prodrug. The parent antitumor agent, 5-FdUrd, was released efficiently from N(3)-FdUrd by hypoxic X-irradiation. On the other hand, the activation of N(3)-FdUrd was suppressed upon X-irradiation under aerobic conditions. A biological assay using A549 cells revealed that the cytotoxicity of N(3)-FdUrd was significantly enhanced by hypoxic X-irradiation.
Asunto(s)
Antineoplásicos/síntesis química , Azidas/síntesis química , Floxuridina/efectos de la radiación , Metano/síntesis química , Profármacos/efectos de la radiación , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/efectos de la radiación , Azidas/química , Azidas/farmacología , Hipoxia de la Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Floxuridina/síntesis química , Floxuridina/química , Humanos , Metano/química , Metano/farmacología , Estructura Molecular , Oxidación-ReducciónRESUMEN
The acetone-sensitized irradiation using UV-B (ultraviolet light, 280-320 nm; sunlamps) of thymidylyl(3'-->5')deoxyfluorouridine monophosphate produces two main photoproducts. The distribution of these photoproducts is dependent on the pH of the irradiation solution. At pH 6, the cis-syn cyclobutane-type photodimer is the major product, whereas at high pH (8-10) a photoadduct is the major product. These photoproducts have been identified and structurally characterized by H-1 and C-13 NMR spectroscopy. The photoadduct arises from defluorination of the 5-fluorouracil moiety. The structure of the photoadduct maintains the sugar-phosphate backbone of the starting material (d-TpF), and contains a saturated thymine moiety with an added Thy(C6-hydroxyl) and a Thy(C5)-(C5)Ura covalent bond.