A CHEMICAL-MODEL FOR THE FRAGMENTATION REACTION IN THYMIDYLATE SYNTHASE CATALYSIS - SYNTHESIS AND EVALUATION OF A LENE-1-(1,2,3,4-TETRAHYDROQUINOLYL)-6-ALLYLURIDINE

Compounds 5 and 6 were synthesized as models to investigate the reacti vity of proposed intermediate 2 in thymidylate synthase (TS) catalysis as it fragments to form dTMP. The mechanism of the fragmentation (hom olytic or heterolytic) of model 6 was determined via subsequent intera ction of the fragmented center with the C6 allyl substituent. The resu lts were consistent with an ionic fragmentation of 6, followed by loss of an allylic proton, and subsequent thermal electrocyclic or Diels-A lder reactions of the resulting trienes 13 and 14, respectively. Indep endent generation of radicals analogous to that produced from a radica l fragmentation of model 6 did not result in formation of trienes 13 a nd 14.