Title

The contribution of a 2-amino group on receptor tyrosine kinase inhibition and antiangiogenic activity in 4-anilinosubstituted pyrrolo[2,3-d]pyrimidines

DOI

10.1016/j.bmcl.2010.03.064

Document Type

Journal Article

Publication Date

5-15-2010

Publication Title

Bioorganic and Medicinal Chemistry Letters

Volume

20

Issue

10

First Page

3177

Last Page

3181

ISSN

0960894X

Keywords

Antitumor agents, Molecular modeling, Structure-activity relationship, Tyrosine kinase inhibitors

Abstract

Comparison between a series of pyrrolo[2,3-d]pyrimidines with and without the 2-amino group is presented in order to determine the validity of our hypothesis that inclusion of this group improves potency against receptor tyrosine kinases (RTK). The 2-amino analogs were better against epidermal growth factor receptor (EGFR) and platelet derived growth factor-β (PDGFR-β) in whole cell inhibition assays and in the A431 cytotoxicity assay compared to the 2-desamino analogs. However, the 2-desamino analogs were more potent inhibitors against vascular endothelial growth factor-2 (VEGFR-2) than the corresponding 2-amino compounds. In addition, none of the 2-desamino compounds exhibited better anti-angiogenic activity in the chorioallantoic membrane (CAM) assay as compared to the standard and were only micromolar inhibitors. This study validates our original hypothesis that the inclusion of a 2-amino group in pyrrolo[2,3-d]pyrimidines improves multiple RTK inhibition and antiangiogenic activity. © 2010 Elsevier Ltd. All rights reserved.

Open Access

Green Accepted

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