Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo
Synthesis and antitumor activities evaluation of m-(4-morpholinoquinazolin-2-yl)benzamides in vitro and in vivo
复制标题
间(4-吗啉代喹唑啉-2-基)苯甲酰胺的合成及体内外抗肿瘤活性评价
DOI：
10.1016/j.ejmech.2015.04.037
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发表时间：
2015-05-26
影响因子：
6.7
通讯作者：
Zhang, San-Qi
中科院分区：
文献类型：
--
作者：
Wang, Xiao-Meng;Xin, Min-Hang;Zhang, San-Qi
本文设计、合成了一系列间-（4-吗啉代喹唑啉-2-基）苯甲酰胺类化合物，并对其结构进行了表征。对两种人细胞系（HCF-116和MCF-7）评价合成的化合物的抗增殖活性。进一步评价IC 50值低于4 μ M的化合物对U-87 MG和A549细胞系的作用。在这些评价的化合物中，化合物T10在体外显示出显著的抗增殖作用。Hoechst染色实验表明化合物T10引起形态学变化。细胞周期和凋亡实验进一步表明，化合物T10可使HCT-116细胞阻滞于G2/M期和G 0/G1期，诱导细胞凋亡。PI 3 K酶测定表明化合物17和T10选择性抑制PI 3 K α。Western bolt测定进一步表明化合物T10可以阻断PI 3 K/Akt/mTOR途径。此外，化合物T10抑制小鼠S180同种移植物模型上的肿瘤生长。这些发现直接鉴定了间-（4-吗啉代喹唑啉-2-基）苯甲酰胺衍生物作为新的抗癌剂。(C)2015年Elsevier Masson SAS。All rights reserved.
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 (HCF-116 and MCF-7). Compounds with IC50 values below 4 mu M 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 17 and T10 selectively inhibit PI3K alpha. 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. (C) 2015 Elsevier Masson SAS. All rights reserved.