Design, synthesis and evaluation of N-hydroxypropenamides based on adamantane to overcome resistance in NSCLC.
Design, synthesis and evaluation of N-hydroxypropenamides based on adamantane to overcome resistance in NSCLC.
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DOI：
10.1016/j.bioorg.2019.02.047
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发表时间：
2019-05
影响因子：
5.1
通讯作者：
Xuefei Bao;Yuhong Sun;Changshun Bao;Jiayu Zhang;Shenglan Zou;Jingyu Yang;Chunfu Wu;Lihui Wang;Guoliang Chen
中科院分区：
文献类型：
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作者：
Xuefei Bao;Yuhong Sun;Changshun Bao;Jiayu Zhang;Shenglan Zou;Jingyu Yang;Chunfu Wu;Lihui Wang;Guoliang Chen
我们鉴定了一系列含有金刚烷基的新型N-羟基丙烯酰胺类化合物，其中大部分具有HDAC抑制活性，并能逆转非小细胞肺癌细胞对顺铂的耐药性。在这个过程中，通过分子对接来验证设计的合理性，随后合成目标化合物并进行基于酶和细胞的生物学评价。大部分合成化合物均能抑制A549细胞的HDAC活性，IC50值低于50 nm，并导致A549细胞中Ac-H4和p21的表达增加。重要的是，我们评估了这些化合物的逆转作用，发现有几个化合物对肺癌细胞具有抗耐药作用，尤其是化合物8f。与贝力诺和顺铂相比，化合物8f对A549/CDDP细胞的抑制活性有所提高，IC50值为5.76 μM，而耐药指数为1.24。此外，还总结了这些化合物的构效关系，化合物8f可作为鉴定耐药逆转机制的研究工具和设计新化合物逆转顺铂耐药的模板。
A series of novelN-hydroxypropenamides containing adamantane moiety were identified and most of them exhibited HDAC inhibitory activity and could reverse the resistance of cisplatin in NSCLC cell lines. In this process, molecular docking was employed to verify the rationality of designing, subsequently, target compounds were synthesized and conducted to enzyme- and cell-based biological evaluation. Most of synthesized compounds could inhibit HDAC activity with the IC50values lower than 50 nM and result in the increase of Ac-H4 and p21 in A549 cells. Importantly, we assessed the reversal effect of those compounds and found several compounds display an anti-resistant effect in lung cancer cells, especially compound8f.As compared to belinostat and cisplatin, compound8fshowed improved inhibitory activity against A549/CDDP cell lines with IC50value of 5.76 μM, and far lower resistance index of 1.24. Moreover, the structure–activity relationships of these compounds were summarized and compound8fcould serve as a research tool for identifying the mechanism of reversing resistance and a template for designing novel compounds to reverse cisplatin resistance.