Discovery of 4-benzoylamino-N-(prop-2-yn-1-yl)benzamides as novel microRNA-21 inhibitors.
MicroRNA-21, as an oncogenic miRNA, has caught great attention for medicinal chemists to develop its novel inhibitors for cancer therapy. In the present study, we designed 4-benzoylamino-N-(prop-2-yn-1-yl)benzamides as miR-21 inhibitor candidates on the basis of scaffold hopping. Eighteen compounds were synthesized. The inhibitory activities of synthesized compounds against the expression of miR-21 were evaluated using stem loop RT-qPCR and compound 1j was discovered as the most potent compound, which displayed a time and concentration dependent inhibition manner. In addition, various functional assays such as the expression of miR-21 target gene detected by Western blotting and the cell growth and apoptosis detected by flow cytometric analysis were checked in Hela (human epithelioid cervix carcinoma) and U-87 MG (human glioblastoma) cells to confirm its activity. The results indicate that compound 1j can enhance apoptosis, retard proliferation, and up-regulate PDCD4, a target protein of miR-21. In addition, the compound 1j does not influence the expression of multiple miRNAs and the genes that participate in miRNA universal biosynthesis pathway. These results strongly support the assumption that title compounds can serve as a small molecule inhibitor of miR-21.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, PR China.
Cong-shan
CS
Jiang
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China.
Xiao-meng
XM
Wang
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China. Electronic address: sqzhang@mail.xjtu.edu.cn.
San-qi
SQ
Zhang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, PR China.
Lie-su
LS
Meng
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, PR China.
Wen-hua
WH
Zhu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, PR China.
Jing
J
Xu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi, PR China. Electronic address: lushemin@mail.xjtu.edu.cn.
She-min
SM
Lu
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins
Benzamide; MicroRNA-21; MicroRNA-21 inhibitor; Scaffold hopping