Synthesis and evaluation of chalcone analogues containing a 4-oxoquinazolin-2-yl group as potential anti-tumor agents
Synthesis and evaluation of chalcone analogues containing a 4-oxoquinazolin-2-yl group as potential anti-tumor agents
复制标题
含有 4-oxoquinazolin-2-yl 基团的查尔酮类似物作为潜在抗肿瘤剂的合成和评估。
DOI：
10.1016/j.ejmech.2018.11.034
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发表时间：
2019-01-15
影响因子：
6.7
通讯作者：
Xu, Xingzhi
中科院分区：
文献类型：
--
作者：
Han, Xue;Peng, Bin;Xu, Xingzhi
查耳酮基序存在于许多有助于重要生物过程的分子中，并且许多含查耳酮的化合物表现出有效的抗癌活性。在这里，我们通过用 4-oxoquinazolin-2-yl 基团取代查耳酮 B 环或 A 环，合成了两个系列的查耳酮类似物（3a-s 和 6a-s），然后评估它们在人结直肠 HCT-116 和乳腺癌 MCF-7 细胞系中的细胞毒活性。根据其抑制增殖的IC50值，化合物3a-s（其中4-氧代喹唑啉-2-基基团充当B环）比化合物6a-s（其中4-氧代喹唑啉-2-基基团充当A环）的细胞毒性明显更高。化合物 3f 被发现是 38 种类似物中最有效的，并对其细胞毒性机制进行了研究。流式细胞术表明，用化合物3f处理的HCT-116细胞导致亚G1期细胞呈剂量依赖性积累，这是凋亡细胞的代表。随后的测定（包括Annexin V-FITC/PI、AO-EB、MitoSOX (TM) Red 和JC-1 染色）证实3f 暴露诱导HCT-116 细胞凋亡。免疫印迹分析表明，细胞暴露于 3f 会增加 PARP1 以及半胱天冬酶 3、7 和 9 的裂解。总之，这种新型查耳酮类似物对培养的癌细胞系具有细胞毒性作用，这可能是通过线粒体死亡途径诱导细胞凋亡来介导的。 (C) 2018 Elsevier Masson SAS。版权所有。
The chalcone motif can be found in many molecules that contribute to essential biological processes, and many chalcone-containing compounds exhibit potent anti-cancer activity. Here, we synthesized two series of chalcone analogues (3a-s and 6a-s) based on substituting the chalcone B-ring or A-ring with a 4-oxoquinazolin-2-yl group, and then evaluated them for cytotoxic activity in human colorectal HCT-116 and breast cancer MCF-7 cell lines. Compounds 3a-s (in which a 4-oxoquinazolin-2-yl group functioned as the B-ring) were markedly more cytotoxic than compounds 6a-s (in which 4-oxoquinazolin-2-yl group functioned as the A-ring), based on their IC50 values to inhibit proliferation. Compound 3f was found as the most potent among 38 analogues and the mechanism of its cytotoxicity was investigated. Flow cytometry indicated that HCT-116 cells treated with compound 3f resulted in a dose-dependent accumulation of cells in the sub-G1 phase, which is representative of apoptotic cells. Subsequent assays (including Annexin V-FITC/PI, AO-EB, MitoSOX (TM) Red and JC-1 staining) confirmed that 3f exposure induced apoptosis in HCT-116 cells. Immunoblotting analysis indicated that cellular exposure to 3f increased the cleavage of PARP1 and caspases 3, 7, and 9. Taken together, this novel chalcone analogue has a cytotoxic effect on cultured cancer cell-lines that is likely mediated by inducing apoptosis via the mitochondrial death pathway. (C) 2018 Elsevier Masson SAS. All rights reserved.