Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo.
In the present study, a series of m-(4-morpholinoquinazolin-2-yl)benzamides were designed, synthesized and characterized. The antiproliferative activities of the synthesized compounds were evaluated against two human cell lines (HCT-116 and MCF-7). Compounds with IC50 values below 4 μM were further evaluated against U-87 MG and A549 cell lines. Among these evaluated compounds, compound T10 displayed a remarkable antiproliferative effect in vitro. The hoechst staining assay showed that compound T10 caused morphological changes. The cell cycle and apoptosis assay further indicated that compound T10 can arrest HCT-116 cells in G2/M and G0/G1 phase and induce apoptosis. PI3K enzyme assays indicated that compounds T7 and T10 selectively inhibit PI3Kα. A Western bolt assay further suggested that compound T10 can block the PI3K/Akt/mTOR pathway. Moreover, compound T10 inhibited tumor growth on a mice S180 homograft model. These findings directly identify m-(4-morpholinoquinazolin-2-yl)benzamide derivatives as novel anticancer agents.
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Xiao-Meng
XM
Wang
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Min-Hang
MH
Xin
Department of Genetics and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an Shaanxi 710061, PR China.
Jing
J
Xu
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Bo-Rui
BR
Kang
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Yan
Y
Li
Department of Genetics and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an Shaanxi 710061, PR China.
She-Min
SM
Lu
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: sqzhang@xjtu.edu.cn.
San-Qi
SQ
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C000604902:3-(6,7-dimethoxy-4-morpholinoquinazolin-2-yl)-5-(trifluoromethoxy)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D011799:Quinazolines
Antitumor agents; Benzamide; PI3K inhibitor; Quinazoline; Synthesis