Synthesis and biological activity of 5-chloro-N4-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic agents
DOI
10.1016/j.bmc.2013.01.040
Document Type
Journal Article
Publication Date
4-1-2013
Publication Title
Bioorganic and Medicinal Chemistry
Volume
21
Issue
7
First Page
1857
Last Page
1864
ISSN
9680896
Keywords
Cytotoxicity, Pyrimido[4, 5-b]indol synthesis, Receptor tryosine kinase inhibitors, VEGFR-2 inhibitors
Abstract
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-N4-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. © 2013 Elsevier Ltd. All rights reserved.
Open Access
Green Accepted
Preprint
Repository Citation
Gangjee, A., Zaware, N., Raghavan, S., Disch, B., Thorpe, J., Bastian, A., & Ihnat, M. (2013). Synthesis and biological activity of 5-chloro-N4-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic agents. Bioorganic and Medicinal Chemistry, 21 (7), 1857-1864. https://doi.org/10.1016/j.bmc.2013.01.040