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Design and Synthesis of 4‐Anilinothieno[2,3‐ d ]pyrimidine‐Based Compounds as Dual EGFR/HER‐2 Inhibitors
Author(s) -
Abd El Hadi Soha R.,
Lasheen Deena S.,
Hassan Mahmoud A.,
Abouzid Khaled A. M.
Publication year - 2016
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201600197
Subject(s) - epidermal growth factor receptor , chemistry , kinase , egfr inhibitors , pyrimidine , cancer research , moiety , growth inhibition , cell culture , cell growth , stereochemistry , receptor , pharmacology , biochemistry , biology , genetics
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 IC 50 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 (IC 50 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.