title: Synthesis, structure, and conformation of anti-tumor agents in the solid and solution states: hydroxyl derivatives of Ftorafur.
abstract: The pyrimidine antimetabolite Ftorafur [FT; 5-fluoro-1-(tetrahydro-2-furyl)uracil] has shown significant antitumor activity in several adenocarcinomas with a spectrum of activity similar to, but less toxic than, 5-fluorouracil (5-FU). It is considered as a prodrug that acts as a depot form of 5-FU, and hence the two drugs exhibit a similar spectrum of chemotherapeutic activity. Ftorafur is metabolized in animals and humans when hydroxyl groups are introduced into the tetrahydrofuran moiety. These metabolites are also thought to be as active as ftorafur but less toxic than 5-FU. Hydroxyl derivatives: 2'-hydroxyftorafur (III), 3'-hydroxyftorafur (IV) and 2',3'-dihydroxyftorafur (II) were synthesized and X-ray and NMR studies of these hydroxyl derivatives were undertaken in our laboratories to study the structural and conformational features of Ftorafur and its metabolites in the solid and solution states. X-ray crystallographic investigations were carried out with data collected on a CAD-4 diffractometer. The structures were solved and refined using the SDP crystallographic package of Enraf-Nonius on PDP 11/34 and Microvax computers. All of the compounds studied had the base in the anti conformation. The glycosidic torsion angles varied from -20 to 60 degrees. There is an inverse correlation between the glycosyl bond distances and the chi angle. Molecules with a lower chi angle have a larger bond distance and vice versa. The sugar rings show a wide variation of conformations ranging from C2'-endo through C3'-endo to C4'-exo. The crystal structures are stabilized by hydrogen bonds involving the base nitrogen atom N3 and the hydroxyl oxygen atoms of the sugar rings as donors and the keto oxygens O2 and O4 of the base and the hydroxyl oxygen atoms O2' and O3' as acceptors. The NMR studies were carried out on Brüker 400 and 600 MHz instruments. Simulated proton spectra were obtained through Laocoon, and pseudorotational parameters were solved by Pseurot. Presence of syn or anti forms was demonstrated with the use of NOE experiments. The glycosyl conformations in solution vary more widely than in the solid state. The conformations of the sugar molecules are in agreement with the values obtained in the solid state. The studies of the structure and conformation in the solid and solution states give a model for the Ftorafur molecule that could be used in structure, function and biological activity correlation studies.
authors.affiliation: Department of Molecular and Cellular Biophysics and Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Stokes
authors.forename: Brajeswar
authors.initials: B
authors.lastname: Paul
authors.forename: James L
authors.initials: JL
authors.lastname: Alderfer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wollman
authors.forename: Thamarapu
authors.initials: T
authors.lastname: Srikrishnan
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D017665:Hydroxyl Radical / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012996:Solutions / Q000737:chemistry; D005641:Tegafur / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000964:Antimetabolites, Antineoplastic; D012996:Solutions; D005641:Tegafur; D017665:Hydroxyl Radical