Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors
DOI
10.1016/j.bmc.2009.08.044
Document Type
Journal Article
Publication Date
10-15-2009
Publication Title
Bioorganic and Medicinal Chemistry
Volume
17
Issue
20
First Page
7324
Last Page
7336
ISSN
9680896
Keywords
Dihydrofolate reductase, EGFR, Multitargeted inhibitors, PDGFR-β
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. © 2009 Elsevier Ltd. All rights reserved.
Open Access
Green Accepted
Preprint
Repository Citation
Gangjee, A., Li, W., Lin, L., Zeng, Y., Ihnat, M., Warnke, L., Green, D., Cody, V., Pace, J., & Queener, S. (2009). Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors. Bioorganic and Medicinal Chemistry, 17 (20), 7324-7336. https://doi.org/10.1016/j.bmc.2009.08.044