Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents.
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Gangjee A, Yu J, Kisliuk RL, Haile WH, Sobrero G, McGuire JJ
Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents.
J Med Chem. 2003 Feb 13;46(4):591-600.
- PubMed ID
- 12570380 [ View in PubMed]
- Abstract
Two novel analogues, N-[2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutam ic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as antitumor agents. Compound 2 had inhibitory potency against human DHFR similar to N-[4-[2-(amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L -glutamic acid (LY231514) and 1, whereas 4 was inactive against human DHFR. Both 2 and 4 were more potent than LY231514 against E. coliTS. Against human TS, 2 was 7-fold less potent than LY231514 and 4 showed similar inhibitory activity as LY231514. In contrast to 2, which was an efficient substrate of human folypolyglutamate synthetase (FPGS), 4 was a poor substrate of FPGS. Compound 2 showed GI50 values in the nanomolar range against more than 18 human tumor cell lines in the standard NCI preclinical in vitro screen.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Methotrexate Dihydrofolate reductase IC 50 (nM) 22 N/A N/A Details Trimethoprim Dihydrofolate reductase IC 50 (nM) 3400 N/A N/A Details