Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents
Bioorganic and Medicinal Chemistry
Antiangiogenic agents, Antitumor agents, Indeno[2, 1-d]pyrimidines, Receptor tyrosine kinase inhibitors
We designed, synthesized and evaluated 13 novel tricyclic indeno[2,1-d]pyrimidines as RTK inhibitors. These analogues were synthesized via a Dieckmann condensation of 1,2-phenylenediacetonitrile followed by cyclocondensation with guanidine carbonate to afford the 2-amino-3,9-dihydro- indeno[2,1-d]pyrimidin-4-one. Sulfonation of the 4-position followed by displacement with appropriately substituted anilines afforded the target compounds. These compounds were potent inhibitors of platelet-derived growth factor receptor β (PDGFRβ) and inhibited angiogenesis in the chicken embryo chorioallantonic membrane (CAM) assay compared to standards. In addition, compound 7 had a two digit nanomolar GI 50 against nine tumor cell lines, a submicromolar GI 50 against 29 of other tumor cell lines in the preclinical NCI 60 tumor cell line panel. Compound 7 also demonstrated significant in vivo inhibition of tumor growth and angiogenesis in a B16-F10 syngeneic mouse melanoma model. © 2012 Elsevier Ltd. All rights reserved.
Gangjee, A., Zhao, Y., Ihnat, M., Thorpe, J., Bailey-Downs, L., & Kisliuk, R. (2012). Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents. Bioorganic and Medicinal Chemistry, 20 (14), 4217-4225. https://doi.org/10.1016/j.bmc.2012.05.068