| The design and synthesis of several monocyclic and bicyclic inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) is described in this study.; This work has culminated in the synthesis of thirty-two novel nonclassical antifolates and one classical antifolate. Thirty-one compounds were submitted for biological evaluation against DHFRs from P. carinii, T. gondii and rat liver. The reversed bridge quinazoline antifolates were evaluated against TS from human, L. casei and P. carinii.; This work also describes attempts towards the synthesis of tricyclic 286. The o-nitrile/guanidine strategy (condensation of guanidine with the appropriate pyrrolo (3,4-c) pyridine) may afford the elusive tricyclic 286. During the attempts towards the synthesis of 5-arylthio-(3H)-4-oxo-(7H)-pyrrolo (2,3-d) pyrimidine analogues of general structure 318, we developed a novel and short synthesis of 2-Pivaloylamido-5-iodo-(3H)-4-oxo-(7H)-pyrrolo (2,3-d) pyrimidine (373). This is a crucial intermediate in the synthesis of LY231514, a novel and potent antifolate.; In the last part of this work the classical furo (2,3-d) pyrimidine 320, was synthesized in an efficient manner, with an excellent yield of the displacement reaction (to afford the thiopteroic ester 406). The entire seven step sequence was carried out without the need for column purification. |
