Abstract
Based on the analysis of epidermal growth factor receptor (EGFR) complexes with gefitinib with molecular docking, the scaffold-hopping strategy, combination of the active substructures, and structural optimization of EGFR inhibitors, a novel series of benzo[4,5]imidazo[2,1-b]thiazole derivatives was designed, synthesized, and evaluated for antitumor activity in human cancer cell lines and cellular toxicity against human normal cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay and EGFR inhibitory activities in vitro. Some target compounds such as 2-(benzo[4,5]imidazo[2,1-b]thiazol-3-yl)-N-(2-hydroxyphenyl)acetamide (D04) and 2-(benzo[4,5]imidazo[2,1-b]thiazol-3-yl)-N-(naphthalen-1-yl)acetamide (D08) have shown significant antitumor activity against the EGFR high-expressed human cell line HeLa. All the target compounds showed hardly any antitumor activity against the EGFR low-expressed human cell line HepG2, and nearly no cellular toxicity against the human normal cell lines HL7702 and human umbilical vein endothelial cell lines (HUVEC). The inhibitory activities against EGFR kinase in vitro of the three target compounds were greatly consistent with the anti-proliferative activities. The preliminary structure–activity relationships of the target compounds were summarized. Conclusively, the novel benzo[4,5]imidazo[2,1-b]thiazole derivatives as novel potential EGFR inhibitors may be used as the potential lead compounds for the development of antitumor agents.
Highlights
22 of and/or mutation of epidermal growth factor receptor (EGFR) plays an important role in the growth of cancer of 13 including cell proliferation, anti-apoptosis, metastasis, and angiogenesis [3]
We report on the synthesis, characterization, and we report on the synthesis, characterization, and biological activity against cancer and normal biological activity against cancer and normal human cell lines of a novel series of human cell lines of a novel series of benzo[4,5]imidazo[2,1-b]thiazole derivatives as EGFR inhibitors
Gefitinib was chosen as the lead to become the
Summary
8.2 million deaths occurred, and by 2030, this statistic is reported to increase to about 19 million [1]. To find an effective way to prevent cancer from developing and stop patients from deteriorating, over the past decade, a novel series of selective chemotherapeutic drugs such as imatinib, gefitinib, erlotinib, and afatinib has been launched worldwide for the treatment of cancer (Figure 1). The action targets of these innovative drugs are mainly directed to impact the signal transduction pathway of the epidermal growth factor receptor (EGFR, Figure 2) [2]. 22 of and/or mutation of EGFR plays an important role in the growth of cancer of 13 including cell proliferation, anti-apoptosis, metastasis, and angiogenesis [3]. The EGFR has been reported attractive target for cancer therapy [4,5,6]
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