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.
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Gangjee A, Zhao Y, Raghavan S, Ihnat MA, Disch BC
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.
Bioorg Med Chem. 2010 Jul 15;18(14):5261-73. doi: 10.1016/j.bmc.2010.05.049. Epub 2010 May 25.
- PubMed ID
- 20558072 [ View in PubMed]
- Abstract
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 alpha-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-beta 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Erlotinib Epidermal growth factor receptor IC 50 (nM) 1200 N/A N/A Details Semaxanib Vascular endothelial growth factor receptor 2 IC 50 (nM) 12900 N/A N/A Details Sunitinib Platelet-derived growth factor receptor beta IC 50 (nM) 12200 N/A N/A Details Sunitinib Vascular endothelial growth factor receptor 2 IC 50 (nM) 18900 N/A N/A Details