Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors.
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Gangjee A, Li W, Lin L, Zeng Y, Ihnat M, Warnke LA, Green DW, Cody V, Pace J, Queener SF
Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors.
Bioorg Med Chem. 2009 Oct 15;17(20):7324-36. doi: 10.1016/j.bmc.2009.08.044. Epub 2009 Aug 22.
- PubMed ID
- 19748785 [ View in PubMed]
- 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 1.4A, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5A) 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-beta were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.
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- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Semaxanib Vascular endothelial growth factor receptor 2 IC 50 (nM) 2400 7.4 37 Details