SYNTHESIS AND BIOLOGICAL EVALUATION OF IN-5-YL]METHYL)THIO]CYCLOBUTYL)BENZOYL]-L-GLUTAMIC ACID A NOVEL 5-THIAPYRIMIDINONE INHIBITOR OF DIHYDROFOLATE-REDUCTASE

The synthesis and biological evaluation of in-5-yl]methyl)thio]cyclobu tyl)benzoyl]-L-glutamic acid (1) is reported. Compound 1 is a potent d ihydrofolate reductase (DHFR) inhibitor (K-i = 12 nM) with excellent i n vitro cell culture growth inhibition (L1210, IC50 = 29 nM). Protecti on experiments showed that the cell growth inhibitory activity was due to DHFR inhibition. The key step in the synthesis was the coupling of a cyclobutylmethylthiol with the 5-bromo-2,6-diamino-4-oxopyrimidine 8.