Synthesis and Antitumor Activity of Erlotinib Derivatives Linked With 1,2,3-Triazole.

Peng Deng,Ge Sun,Jie Zhao,Lizeng Peng,Kaitai Yao,Miaomiao Yuan,Longfei Mao

doi:10.3389/fphar.2021.793905

Abstract

Cervical cancer is one of the most important cause of cancer-related death and presents a major public health problem in many countries. To search for more novel antitumor agents against cervical cancer, 14 erlotinib-linked 1,2,3-triazole compounds were designed, synthesized, and evaluated for their anti-tumor activity. The compounds were confirmed by 1H NMR, 13C NMR, and high-resolution mass spectra (HR MS). Antitumor activity assay results indicated that six of those compounds have remarkable inhibitory activity against human cervical cancer HeLa cells in vitro, among which compound 4m was the most potent with IC50 of 3.79 μM, and compounds 4k, 4i, 4l, 4d, and 4n also demonstrated remarkable antitumor activity with IC50 of 3.79, 4.16, 4.36, 7.02, and 8.21 μM. We found three of the most potent compounds 4d, 4k, and 4l induced potent apoptosis and cell cycle arrest in HeLa cells, and compounds 4d and 4l significantly restrained the cell colony formation and showed moderate epidermal growth factor receptor (EGFR) inhibitory activity with IC50 of 13.01 and 1.76 μM. Therefore, these experiments indicate that these erlotinib-linked 1,2,3-triazole compounds are potential to act as effective anticancer agents against cervical cancer.

Highlights

Among women, cervical cancer ranks fourth for both incidence (6.6%) and mortality (7.5%) and is one of the most important cause of cancer-related death (Bray et al, 2018)
We found three of the most potent compounds 4d, 4k, and 4l induced potent apoptosis and cell cycle arrest in HeLa cells, and compounds 4d and 4l significantly restrained the cell colony formation and showed moderate epidermal growth factor receptor (EGFR) inhibitory activity with IC50 of 13.01 and 1.76 μM
Epidermal growth factor receptor (EGFR) is a protein tyrosine kinase transmembrane receptor encoded by proto-oncogene HER-1 (Roskoski 2014) and is overexpressed in a variety of cancers such as breast, cervical, liver, and non-small cell lung cancers

Summary

Introduction

Cervical cancer ranks fourth for both incidence (6.6%) and mortality (7.5%) and is one of the most important cause of cancer-related death (Bray et al, 2018). Even if human papilloma virus (HPV) vaccination were approved and early screening efforts have been made, cervical cancer still represents a major public health problem in many countries due to increased percentage of locoregional and distant recurrences in advanced-inoperable cervical cancer. Recurrent cervical cancer is not amenable to radical treatment, and de novo metastatic disease are considered incurable with poor prognosis (Liontos et al, 2019; Hill 2020). New active anticancer agents and their optimal combinations treatment are desperately needed. Epidermal growth factor receptor (EGFR) is a protein tyrosine kinase transmembrane receptor encoded by proto-oncogene HER-1 (Roskoski 2014) and is overexpressed in a variety of cancers such as breast, cervical, liver, and non-small cell lung cancers.

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Conclusion