PROTEIN STRUCTURE-BASED DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF 5-THIA-2,6-DIAMINO-4(3H)-OXOPYRIMIDINES - POTENT INHIBITORS OF GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE WITH POTENT CELL-GROWTH INHIBITION

The design, synthesis, biochemical, and biological evaluation of a nov el series of 5-thia-2,6-diamino-4(3H)-oxopyrimidine inhibitors of glyc inamide ribonucleotide transformylase (GART) are described. The compou nds were designed using the X-ray crystal structure of human GART. The monocyclic 5-thiapyrimidinones were synthesized by coupling an alkyl thiol with 5-bromo-2,6-diamino-4(3H)-pyrimidinone, 20. The bicyclic co mpounds were prepared in both racemic and diastereomerically pure form s using two distinct synthetic routes. The compounds were found to hav e human GART K(i)s ranging from 30 mu M to 2 nM. The compounds inhibit ed the growth of both L1210 and CCRF-CEM cells in culture with potenci es down to the low nanomolar range and were found to be selective for the de novo purine biosynthesis pathway. The most potent inhibitors ha d 2,5-disubstituted thiophene rings attached to the glutamate moiety. Placement of a methyl substituent at the 4-position of the thiophene r ing to give compounds 10, 18, and 19 resulted in inhibitors with signi ficantly decreased mFBP affinity.