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 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.
Original language | English (US) |
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Pages (from-to) | 5261-5273 |
Number of pages | 13 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 18 |
Issue number | 14 |
DOIs | |
State | Published - Jul 15 2010 |
Keywords
- Antiangiogenic agents
- Multiple receptor
- Tyrosine kinase inhibitors
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry