As part of an ongoing program to exploit new strategies of drug design for the preparation of novel chemotherapeutic agents, it is proposed that some mechanism-based inhibitors of three ligases in the nucleotide biosynthetic pathways be synthesized. The target enzymes are GMP synthetase, CTP synthetase, and succino-AICAR synthetase. The inhibitors proposed for each enzyme are in two primary classes: stable analogs of phosphorylated or adenylated intermediates in the reaction pathway, and stable analogs of the tetrahedral intermediates formed after attack of those phosphorylated intermediates by the amine co-substrate. This will involve synthesis of nucleotide analogs containing phosphonomethyl group on the heterocycle in the first case and usually sulfoximines or phosphonates at the sight of reactivity in the second case. These studies should be directly applicable to design of new anticancer agents (all compounds produced will be tested for that activity). In addition, the studies on these compounds as enzyme inhibitors should aid in the understanding of the catalytic mechanism of the enzymes mentioned above.
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