文献类型：期刊文献

英文题名：Discovery of a Novel Potent Antitumor Molecule, P19G1, by Erlotinib Derivative Libraries Synthesized by Modular Click-Chemistry

作者：Cui, Qianfei[1,2];Song, Peng[1,2,3];Ma, Tiancheng[4];Wang, Zefeng[1,2];Lu, Xiaojing[1,2];Shi, Yongjia[1,2];Zhang, Fang[1,2];Lin, Guoqiang[1,2,4];Dong, Jiajia[4];Zhang, Jiange[1,2]

第一作者：Cui, Qianfei

通信作者：Zhang, JG[1];Zhang, JG[2];Dong, JJ[3]

机构：[1]Shanghai Univ Tradit Chinese Med, Res Ctr Chiral Drugs, Shanghai 201203, Peoples R China;[2]Shanghai Univ Tradit Chinese Med, Shanghai Frontiers Sci Ctr Tradit Chinese Med Che, Innovat Res Inst Tradit Chinese Med IRI, Shanghai 201203, Peoples R China;[3]Gansu Univ Chinese Med, Affiliated Hosp, Key Lab Prevent & Treatment Chron Dis, Lanzhou, Gansu, Peoples R China;[4]Chinese Acad Sci, Shanghai Inst Organ Chem, Shanghai 200032, Peoples R China

第一机构：Shanghai Univ Tradit Chinese Med, Res Ctr Chiral Drugs, Shanghai 201203, Peoples R China

通信机构：[1]corresponding author), Shanghai Univ Tradit Chinese Med, Res Ctr Chiral Drugs, Shanghai 201203, Peoples R China;[2]corresponding author), Shanghai Univ Tradit Chinese Med, Shanghai Frontiers Sci Ctr Tradit Chinese Med Che, Innovat Res Inst Tradit Chinese Med IRI, Shanghai 201203, Peoples R China;[3]corresponding author), Chinese Acad Sci, Shanghai Inst Organ Chem, Shanghai 200032, Peoples R China.

年份：2022

卷号：21

外文期刊名：TECHNOLOGY IN CANCER RESEARCH & TREATMENT

收录：;Scopus(收录号：2-s2.0-85140862336);WOS:【SCI-EXPANDED(收录号:WOS:000885840900001)】；

语种：英文

外文关键词：click chemistry; antitumor; Erlotinib; drug discovery

摘要：Objective:Traditional chemical synthesis methods are cumbersome and inefficient. In this study, a novel antitumor molecule, 4-(4-(3-((6,7-bis(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)phenyl sulfurofluoridate (P19G1), was identified by screening a library of Erlotinib derivatives synthesized by modular click chemistry, and the antitumor activity and underlying mechanism of P19G1 were further revealed. Methods: A series of Erlotinib derivatives (840 compounds) were synthesized using a modular click-chemistry method, and then the thiazolyl blue (MTT) method was used to screen and evaluate the inhibitory effect of these compounds on the growth and metastasis of A549 lung adenocarcinoma cells. Among them, the compound P19G1 showed the best inhibitory activity. Furthermore, the antitumor activity and mechanism of P19G1 were investigated with in vitro cell biology and in vivo assays in an animal model. Results: In vitro pharmacological studies showed that P19G1 had inhibitory effects on a variety of tumor cell lines with IC50 values in the range of 1 to 5 mu M. Moreover, P19G1 significantly inhibited the proliferation and migration of the human lung adenocarcinoma cell line A549 and human colorectal cancer cell line RKO and promoted cell apoptosis. In vivo tumor-bearing mouse model experiments revealed that 50 mg/kg P19G1 effectively inhibited the growth and metastasis of A549 tumors without obvious toxicity to the host. Conclusions: The rapid structural modification of lead compounds using novel modular click-chemistry reactions holds great potential for use in obtaining diverse derivatives for tumor drug screening and development. P19G1 was discovered because of the application of click chemistry in this study, and it is an antitumor candidate molecule worthy of development.