MEDI 64 |
| In mammals aspartate transcarbamoylase (ATCase) is a portion of a multifunctional enzyme (CAD) which is required for de novo pyrimidine nucleotide biosynthesis. The ATCase portion of CAD catalyzes the second step in pyrimidine nucleotide biosynthesis, the reaction between carbamoyl phosphate and L-aspartate to give N-carbamoyl-L-aspartate and inorganic phosphate. ATCase has become a target for the development of anti-proliferative drugs and inhibitors of ATCase are considered as potential anti-tumor agents, since the levels of ATCase have been shown to be elevated in cancer cells. Here we report the synthesis and bioactivity of a series of inhibitors of the ATCase. These inhibitors are analogues of a highly potent inhibitor of this enzyme, N-phosphonacetyl-L-aspartate (PALA). Analogues have been synthesized with modifications at the alpha- and beta-carboxylates as well as at the aspartate moiety. The ability of these compounds to inhibit the enzyme was evaluated. These studies, with functional group modified PALA derivatives, showed that amide groups can be a useful substitute of the carboxylate in order to reduce the charge on the molecule, and indicate that the relative position of the functional group in the beta-position is more critical than the nature of the functional group. Some of the molecules synthesized here are potent inhibitors of the enzyme. |
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Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Sci-Mix
Division of Medicinal Chemistry |