Design, synthesis and evaluation of 2-amino-4-m-bromoanilino-6-arylmethyl- 7H-pyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors and antiangiogenic agents
Bioorganic and Medicinal Chemistry
Antiangiogenic agents, Multiple receptor, Tyrosine kinase inhibitors
A series of 2-amino-4-m-bromoanilino-6-benzyl pyrrolo[2,3-d]pyrimidines analogues 4-12 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). These analogues were synthesized from the appropriate α-bromomethylbenzylketones via cyclocondensation with 2,6-diamino-4- pyrimidone to afford the 2-amino-4-oxo-6-substituted benzyl pyrrolo[2,3-d] pyrimidines. Chlorination at the 4-position followed by displacement with 3-bromoaniline or 3-bromo-N-methylaniline and methylation of the 7-NH afforded the target compounds. Remarkably, dimethylation of both the 4-N and N7 afford whole cell EGFR inhibitors that are more cytotoxic than clinically used erlotinib and mono-methylation at the 4-N or N7 affords more cytotoxic whole cell PDGFR-β inhibitors than clinically used sunitinib. Methylation at either the 4-N or N7 position was detrimental to whole cell VEGFR-2 inhibition. The inhibitory data against the RTKs in this study demonstrates that methylation of the 4-NH and/or the 7-NH influences both the specificity and potency of RTK inhibition. © 2010 Elsevier Ltd. All rights reserved.
Gangjee, A., Zhao, Y., Raghavan, S., Ihnat, M., & Disch, B. (2010). Design, synthesis and evaluation of 2-amino-4-m-bromoanilino-6-arylmethyl- 7H-pyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors and antiangiogenic agents. Bioorganic and Medicinal Chemistry, 18 (14), 5261-5273. https://doi.org/10.1016/j.bmc.2010.05.049