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

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 IC 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 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.

Fragment merging approach for design, synthesis, and biological assessment of urea/acetyl hydrazide clubbed thienopyrimidine derivatives as GSK-3β inhibitors

“…The progress of reaction was monitored by TLC, after completion of disappearance of starting materials, cooled the reaction mixture to ambient temperature and the resulting solids were filtered and dried under vacuum. The obtained crude solid was further purified by recrystallization by ethanol to afford desired compound- 1 ( 9.76 g, yield: 80.1% ) as a yellow crystal [ 24 ].…”

Design and Efficient Synthesis of New 4-Amino-Substituted 2-(4-Bromobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines of Anticancer Interest and Their In Silico Study

“…Some of these compounds are summarised in Figure 2. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] Interestingly, it has been noted that 4-amino substituents, whether aryl/aryl alkyl or urea, play a crucial role in binding to cancer proteins. These findings, particularly regarding the 6-membered ring fused theino [2,3-d]pyridines and their medicinal properties, prompted us to develop a more efficient delivery system for new 4-amino substituted 5,6,7,8tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidines.…”

Recent updates on thienopyrimidine derivatives as anticancer agents

“…In 2016, Abd El Hadi et al reported the synthesis of two series of 4-anilinothieno[2,3-d] pyrimidines which were assessed as dual EGFR/HER2 kinase inhibitors (Fig. 8) [87]. Series A contains compounds that were less potent inhibitors for EGFR/HER2 kinase than Series B.…”