Design and Synthesis of 4 ‐Anilinothieno[2,3‐d]pyrimidine‐Based Compounds as Dual EGFR/HER‐2 Inhibitors

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. Anilinothienopyrimidine derivatives bearing the benzyloxy moiety, bulky arylpyridinyl, and arylpyrazolyl moieties at the 4′ position of the anilinothienopyrimidine core were synthesized and evaluated as dual EGFR/HER‐2 inhibitors. N‐(3‐Chloro‐4‐((3‐fluorobenzyl)oxy)phenyl)‐5,6,7,8‐tetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4‐amine (8f) displayed the most potent inhibitory activity on both EGFR and HER‐2 with IC50 equal to 0.2 and 0.5 µM, respectively.
Source: Archiv der Pharmazie - Category: Drugs & Pharmacology Authors: Tags: Full Paper Source Type: research