SYNTHESIS AND BIOCHEMISTRY OF ASCORBIC ACID ANALOGUES

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Ascorbic acid (vitamin C), a dietary requirement for human health, is an electron donor for several enzymatic actions, functions as an antioxidant, and is implicated in host defense mechanisms, endocrine function and the visual process (lens). Recent renewed interest in the biochemistry of ascorbic acid has been prompted by the realization that relatively little is known concerning the concentrations of the vitamin required for optimum functioning of these several roles. In the case of enzymatic reactions, optimal rate of a process is defined as that concentration that allows the reaction to reach Vmax without toxicity. As part of a program to determine these concentrations, in situ kinetic measurements have been carried out for certain vitamin C-linked reactions. In addition to examination of functional roles of vitamin C, recent characterization of efficient transport mechanisms that translocate vitamin C across cellular membranes has emphasized the importance of the vitamin to biological processes. Kinetic parameters of these transport mechanisms are also being determined. The above work, carried out in the Nutrition Program, LCBG, NIDDK, has produced valuable information related to vitamin C biochemistry and metabolism, and has practical implications regarding dietary requirements. However, as in any biochemical study, structural analogues of the natural substrate would be extremely useful to further characterize substrate-macromolecule interactions, by functioning as inhibitors of transport processes, as enzyme inhibitors, and as potential agents for covalent labeling of the functional proteins involved in these processes. Unfortunately, relatively little synthetic work has been carried out on structural modifications of vitamin C. Examples of previous work include the preparation of 6-halo-6-deoxy- and 6-deoxy-ascorbic acid analogues, and 3- or 4-O-alkyl ethers of ascorbic acid. As part of a program to study the effects of structural modification on vitamin C function and to provide biochemical tools for vitamin C research, we have prepared the known 6-halo-6-deoxy analogues and have initiated kinetic measurements of transport inhibition of these analogues. In addition, we have developed reactions that should provide routes to new analogues that can function as affinity labels, radiotracers, and NMR probes.