The long range goal of this work is to develop new classes of amino acids as potential inhibitors for amino acid decarboxylases. This class of enzymes ranks as one of the most important from the point of view of rational drug design. For example, irreversible inhibitors of ornithine decarboxylase and S-adenosylmethionine decarboxylase block the polyamine pathway required for rapid cell proliferation and thereby act as antineoplastic agents. The multi-million dollar antihypertensive drug, Aldomet, is an inhibitor of DOPA decarboxylase. Carbidopa, a peripheral DOPA decarboxylase inhibitor, is used in combination with L-DOPA for the treatment of Parkinson's disease. A new, efficient synthesis of racemic alpha-vinyl amino acids from the corresponding amino acids has been developed in these laboratories. Proposed is the extension of this methodology to the synthesis of optically pure D- and L-alpha-vinyl amino acids. Asymmetry will be induced through the use of a chiral auxiliary in the initial alkylation step or through chemical or enzymatic resolution of the racemic alpha- vinyl amino acids. New inhibitors will be tested for decarboxylase inhibition using steady state enzyme kinetics or a Kitz-Wilson analysis as appropriate to establish mode and potency of inhibition. Promising inhibitors will be submitted to the NCI for cytotoxicity assays.
