Design and Synthesis of 4‐Anilinothieno[2,3‐d]pyrimidine‐Based Compounds as Dual EGFR/HER‐2 Inhibitors
- 13 October 2016
- journal article
- research article
- Published by Wiley in Archiv der Pharmazie
- Vol. 349 (11) , 827-847
Abstract
Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER‐2) is an attractive cancer therapeutic approach. In this study, new series of 4‐anilinothieno[2,3‐d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER‐2 kinase inhibitors. Five compounds (8a, 8b, 8e–g) demonstrated low to submicromolar inhibition of both kinases with IC50 values of 1.2, 0.6, 0.3, 0.2, 0.4 μM and 8.2, 3.4, 1.3, 0.5, 2.7 μM for the EGFR and HER‐2, respectively. Introduction of a 5,6‐tetramethylene moiety into the thienopyrimidine core bearing a 4‐(3‐fluorobenzyloxy)‐3‐chloroaniline tail resulted in a favorable increase in both the EGFR and HER‐2 inhibitory activities. Compound 8f (IC50 EGFR/HER‐2: 0.2/0.5 μM) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non‐small‐cell lung cancer, and renal cancer cell lines.Keywords
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