Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors

Aleem Gangjee, Wei Li, Lu Lin, Yibin Zeng, Michael Ihnat, Linda A. Warnke, Dixy W. Green, Vivian Cody, Jim Pace, Sherry Queener

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

To optimize dual receptor tyrosine kinase (RTK) and dihydrofolate reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 and 1.4 Å, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5 Å) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 2-13 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8-C9 unsaturated compounds 2-7 and catalytic reduction gave the saturated 8-13. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-β were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.

Original languageEnglish
Pages (from-to)7324-7336
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number20
DOIs
StatePublished - Oct 15 2009

Fingerprint

Folic Acid Antagonists
Pyrimidines
Tetrahydrofolate Dehydrogenase
Protein-Tyrosine Kinases
Crystal structure
X-Rays
X rays
Isomers
Unsaturated compounds
Diamines
Receptor Protein-Tyrosine Kinases
Ketones
NADP
High Pressure Liquid Chromatography

Keywords

  • Dihydrofolate reductase
  • EGFR
  • Multitargeted inhibitors
  • PDGFR-β

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors. / Gangjee, Aleem; Li, Wei; Lin, Lu; Zeng, Yibin; Ihnat, Michael; Warnke, Linda A.; Green, Dixy W.; Cody, Vivian; Pace, Jim; Queener, Sherry.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 20, 15.10.2009, p. 7324-7336.

Research output: Contribution to journalArticle

Gangjee, Aleem ; Li, Wei ; Lin, Lu ; Zeng, Yibin ; Ihnat, Michael ; Warnke, Linda A. ; Green, Dixy W. ; Cody, Vivian ; Pace, Jim ; Queener, Sherry. / Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 20. pp. 7324-7336.
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AU - Cody, Vivian

AU - Pace, Jim

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