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-glutamic 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Division / drug effects
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Escherichia coli / chemistry
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Folic Acid Antagonists / chemical synthesis
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Folic Acid Antagonists / chemistry
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Folic Acid Antagonists / pharmacology
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Glutamic Acid / analogs & derivatives
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Glutamic Acid / chemical synthesis*
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Glutamic Acid / chemistry
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Glutamic Acid / pharmacology
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Humans
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Lacticaseibacillus casei / chemistry
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Peptide Synthases / metabolism
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Structure-Activity Relationship
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Tetrahydrofolate Dehydrogenase / metabolism*
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Thymidylate Synthase / antagonists & inhibitors*
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Folic Acid Antagonists
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N-(2-amino-4-ethyl((pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoyl)glutamic acid
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N-(2-amino-4-ethyl-6-methyl((pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoyl)glutamic acid
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Pyrimidines
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Glutamic Acid
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Tetrahydrofolate Dehydrogenase
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Thymidylate Synthase
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Peptide Synthases
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folylpolyglutamate synthetase