Design, Synthesis and Biological Evaluation of a Novel Series of Indole-3- Carboxamide Derivatives for Cancer Treatment as EGFR Inhibitors

Title:Design, Synthesis and Biological Evaluation of a Novel Series of Indole-3- Carboxamide Derivatives for Cancer Treatment as EGFR Inhibitors

Volume: 15 Issue: 1

Author(s): Lan Zhang, Xin-Shan Deng, Guang-Peng Meng, Chao Zhang, Cong-Chong Liu, Gu-Zhou Chen , Xu-Liang Jiang*, Qing-Chun Zhao and Chun Hu*

Affiliation:

• Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016,China

• Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016,China

Keywords: Synthesis, indole-3-carboxamide derivatives, EGFR inhibitors, anticancer activity, structure-activity relationship, cancer.

Abstract: Background: As reported EGFR is a sialoglycoprotein with tyrosine kinase activity involved in control of cellular survival, multiplication, differentiation and metastasis. Dysregulation or aberrant expression of EGFR has been implicated in cell transformation and having oncogenic roles in a number of human cancers. Therefore EGFR has become a significant target for developing targeted therapy for cancer.

Methods: A novel series of indole-3-carboxamide derivatives as EGFR inhibitors were designed, synthesized and evaluated for the anticancer activity in vitro against three EGFR high-expressed cancer cell lines (A549, HeLa, and SW480), one EGFR low-expressed cell line (HepG2) and one human liver normal cell line (HL7702) by MTT assay.

Results: The target compounds 6c, 6f, 6i, 6j, 6l, 6r, 6u and 6x exhibited potent anticancer activities against the three tested cancer cell lines and weak cytotoxic effects on HepG2, which imply that the target compounds are probably effective in inhibiting EGFR. And they also did not show measurable activities in HL7702, which imply the target compounds are likely to overcome the nonspecific toxicity against normal cells. Particularly, the target compound 6x indicated equal to the positive control erlotinib. In addition, molecular docking studies demonstrated the target compound 6x may be the potential inhibitor to EGFR.

Conclusion: A new EGFR inhibitor scaffold and a preliminary discussion on their SARs provide promising opportunities to guide further research on indole-3-carboxamide derivatives as novel anticancer agents.

Cite this article as:

Zhang Lan , Deng Xin-Shan , Meng Guang-Peng , Zhang Chao , Liu Cong-Chong , Chen Gu-Zhou , Jiang Xu-Liang *, Zhao Qing-Chun and Hu Chun *, Design, Synthesis and Biological Evaluation of a Novel Series of Indole-3- Carboxamide Derivatives for Cancer Treatment as EGFR Inhibitors, Letters in Drug Design & Discovery 2018; 15 (1) . https://dx.doi.org/10.2174/1570180814666170929093258