Of the more potent cytotoxic amino acid analogues with antitumor activity, 6-diazo-5-oxo-L-norleucine (DON, NSC 7365) and acivicin (NSC 163501, AT-125) are antagonists of L-glutamine (24) (azaserine, another such antagonist, is not in the standard agent database). In vitro, these antimetabolites are potent inhibitors of several glutamine-dependent amidotransferases, resulting in inhibition of de novo purine biosynthesis (25). DON inhibits N-formylglycineamidine (FGAM) ribotide synthetase, cytidine triphosphate (CTP) synthetase, and glucosamine-6-phosphate isomerase (24, 25). Acivicin is a potent inhibitor of CTP and guanine monophosphate synthetases and partially inhibits FGAM synthetase (24, 26). Both compounds also have in common the inhibition of carbamyl phosphate synthetase II (25 26), the glutamine-hydrolyzing first enzyme of de novo pyrimidine biosynthesis.
In the Table, DON was used as a seed for COMPARE. AT-125 was the closest match (PCC = 0.811). The dihyroorotate dehydrogenase inhibitor brequinar wasthe next closest match. This was followed by the antifolates methotrexate and trimetrexate and the other dihydroorotate dehydrogenase inhibitor, dichloroallyl lawsone. These results suggest that sensitivity to inhibition of cellular nucleotide synthesis is a determinant that characterizes the cell lines affected by these agents.
| Compound | NSC Number | 2D Structure | 3D Structure | Cell Inhibition Data |
|---|---|---|---|---|
| DON | 7365 | 2D | 3D | Cell Data |
| acivicin | 163501 | 2D | 3D | Cell Data |