N2-Trimethylacetyl substituted and unsubstituted-N 4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d] pyrimidine-2,4-diamines: Design, cellular receptor tyrosine kinase inhibitory activities and in vivo evaluation as antiangiogenic, antimetastatic and antitumor agents

DOI

10.1016/j.bmc.2012.12.045

Document Type

Journal Article

Publication Date

3-1-2013

Publication Title

Bioorganic and Medicinal Chemistry

Volume

21

Issue

5

First Page

1312

Last Page

1323

ISSN

9680896

Keywords

Antiangiogenic, Antimetastatic, In vivo, Sonogashira coupling

Abstract

Six novel N4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamines and their N2-trimethylacetyl substituted analogs were synthesized as receptor tyrosine kinase (RTK) inhibitors. A microwave-mediated Sonogashira reaction was used as a key step for the synthesis of these compounds. Biological evaluation, in whole cell assays, showed that some analogs had remarkable inhibitory activity against a variety of RTKs and in particular cytotoxic activity against A431 tumor cells in culture. The inhibitory data against RTKs in this study demonstrated that variation of the 4-anilino substituents of these analogs dictates both potency and specificity of inhibitory activity against various RTKs. The study also supported the hypothesis that interaction of substituents on the 2-amino group with hydrophobic site-II provides an increase in potency. Compound 8 of this series was selected for evaluation in vivo in a B16-F10 syngeneic mouse tumor model and exhibited significant reduction in tumor growth rate, in tumor vascular density and in metastases to the lung compared to the control. © 2012 Elsevier Ltd. All rights reserved.

Open Access

Green Accepted

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