This program has as its primary objective the design and synthesis of inhibitors of S-adenosylmethionine (AdoMet)-dependent methylations as potential experimental or chemotherapeutic agents. Two approaches will be taken to accomplish this objective: (1) the design of S-adenosylhomocysteine (AdoHcy9 analogs that will selectively bind to specific methyltransferases; and (2) the design of adenosine analogs that will inhibit AdoHcy hydrolase, thereby raising the intracellular level of this natural methylase inhibitor. The AdoHcy analogs will be evaluated as inhibitors of a series of purified small molecule methyltransferases (e.g., catechol-O-methyltransferase, phenylethanolamine N-methyltransferase, histamine N-methyltransferase, hydroxyindole O-methyltransferase, aminopropyltransferases etc.) and a series of purified macrmolecule methyltransferases (e.g., t-RNA methylases, mRNA methylases, protein methylases, phospholipid methylases, etc.). The adenosine analogs will be evaluated on purified bovine AdoHcy hydrolase. Both the AdoHcy and adenosine analogs will be evaluated for their ability to inhibit catecholamine metabolism in neuroblastoma cells, vaccinia virus replication in L-cells, leucocyte chemotaxis and secretion from hypothalamic synaptosomes and isolated perfused cat spleen. Studies will also be carried out to determine the active site of histamine-N-methyltransferase and AdoHcy hydrolase using affinity labeling reagents and to determine their catalytic transition states using isotopic probes.
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