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. doi: 10.1021/jm0203534.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / chemistry
  • Folic Acid Antagonists / chemical synthesis
  • Folic Acid Antagonists / chemistry
  • Folic Acid Antagonists / pharmacology
  • Glutamic Acid / analogs & derivatives
  • Glutamic Acid / chemical synthesis*
  • Glutamic Acid / chemistry
  • Glutamic Acid / pharmacology
  • Humans
  • Lacticaseibacillus casei / chemistry
  • Peptide Synthases / metabolism
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Tetrahydrofolate Dehydrogenase / metabolism*
  • Thymidylate Synthase / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Folic Acid Antagonists
  • N-(2-amino-4-ethyl((pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoyl)glutamic acid
  • N-(2-amino-4-ethyl-6-methyl((pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoyl)glutamic acid
  • Pyrimidines
  • Glutamic Acid
  • Tetrahydrofolate Dehydrogenase
  • Thymidylate Synthase
  • Peptide Synthases
  • folylpolyglutamate synthetase