title: Stereoelectronic effect on one-electron reductive release of 5-fluorouracil from 5-fluoro-1-(2-oxocycloalkyl)uracils as a new class of radiation-activated antitumor prodrugs.
abstract: A series of 5-fluoro-1-(2'-oxocycloalkyl)uracils (3-11) that are potentially novel radiation-activated prodrugs for the radiotherapy of hypoxic tumor cells have been synthesized to evaluate a relationship between the molecular structure and the reactivity of one-electron reductive release of antitumor 5-fluorouracil (1) in anoxic aqueous solution. All the compounds 3-11 bearing the 2'-oxo group were one-electron reduced by hydrated electrons (eaq-) and thereby underwent C(1')-N(1) bond dissociation to release 5-fluorouracil 1 in 47-96% yields upon radiolysis of anoxic aqueous solution, while control compounds (12, 13) without the 2'-oxo substituent had no reactivity toward such a reductive C(1')-N(1) bond dissociation. The decomposition of 2-oxo compounds in the radiolytic one-electron reduction was more enhanced, as the one-electron reduction potential measured by cyclic voltammetry in N,N-dimethylformamide became more positive. The efficiency of 5-fluorouracil release was strongly dependent on the structural flexibility of 2-oxo compounds. X-ray crystallographic studies of representative compounds revealed that the C(1')-N(1) bond possesses normal geometry and bond length in the ground state. MO calculations by the AM1 method demonstrated that the LUMO is primarily localized at the pi* orbital of C(5)-C(6) double bond of the 5-fluorouracil moiety, and that the LUMO + 1 is delocalized between the pi* orbital of 2'-oxo substituent and the sigma* orbital of adjacent C(1')-N(1) bond. The one-electron reductive release of 5-fluorouracil 1 in anoxic aqueous solution was presumed to occur from the LUMO + 1 of radical anion intermediates possessing a partial mixing of the antibonding C(2')=O pi* and C(1')-N(1) sigma* MO's, that may be facilitated by a dynamic conformational change to achieve higher degree of (pi* + sigma*) MO mixing.
authors.affiliation: Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.forename: H
authors.initials: H
authors.lastname: Hatta
authors.forename: S
authors.initials: S
authors.lastname: Nishimoto
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000528:radiation effects*; D018360:Crystallography, X-Ray; D004583:Electrons; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000528:radiation effects; D005609:Free Radicals / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction / Q000528:radiation effects; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000528:radiation effects*; D012996:Solutions; D014965:X-Rays
chemical_list: D000970:Antineoplastic Agents; D005609:Free Radicals; D011355:Prodrugs; D012996:Solutions; D005472:Fluorouracil