Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 7, Pages 1857-1864Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.01.040
Keywords
Receptor tryosine kinase inhibitors; Pyrimido[4,5-b]indol synthesis; Cytotoxicity; VEGFR-2 inhibitors
Funding
- National Institutes of Health
- National Cancer Institute [CA98850]
- Duquesne University Adrian Van Kaam Chair in Scholarly Excellence
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Inhibition of receptor tyrosine kinase (RTK) signaling pathways is an important area for the development of novel anticancer agents. Numerous multikinase inhibitors (MKIs) have been recently approved for the treatment of cancer. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the principal mediator of tumor angiogenesis. In an effort to develop ATP-competitive VEGFR-2 selective inhibitors the 5-chloro-N-4-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamine scaffold was designed. The synthesis of the target compounds involved N-(4,5-dichloro-9H-pyrimido[4,5-b]indol-2-yl)-2,2-dimethylpropanamide) as a common intermediate. A nucleophilic displacement of the 4-chloro group of the common intermediate by appropriately substituted anilines afforded the target compounds. Biological evaluation indicated that compound 5 is a potent and selective VEGFR-2 inhibitor comparable to sunitinib and semaxinib. (C) 2013 Elsevier Ltd. All rights reserved.
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