Analogs of intermediates in the de novo purine nucleotide biosynthetic pathway were synthesized to study the binding requirements of the corresponding enzymes. Because of the instability of the natural substrates, such as phosphoribosylamine, the use of the structurally stable phosphonate moiety and the carbocyclic ribose yields ideal analogs for these studies. In addition, these analogs can act as potential inhibitors of the de novo pathway leading to the design of anticancer agents. Enzyme studies with GAR synthetase and GAR transformylase reveal that the title compounds can act as substrates or inhibitors of the de novo enzymes.
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Acknowledgments. This work was supported by National Institutes of Health Grants KO1 CA23263 (R.V.), R01 GM46243 (C.A.C.), and KO1 GM42663 (C.A.C.)