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首页> 外文期刊>Journal of Cellular Physiology >Design, synthesis, and characterization of α, β‐unsaturated carboxylic acid, and its urea based derivatives that explores novel epigenetic modulators in human non‐small cell lung cancer A549 cell line
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Design, synthesis, and characterization of α, β‐unsaturated carboxylic acid, and its urea based derivatives that explores novel epigenetic modulators in human non‐small cell lung cancer A549 cell line

机译：设计、合成和表征的α,基于地理β不饱和羧酸,尿素衍生品,探索小说表观遗传调节器在人类非小细胞肺癌A549细胞株

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Histone deacetylase inhibitors (HDACi) are a small molecule chemotherapeutics that target the chromatin remodeling through the regulation of histone and non‐histone proteins. These inhibitors directed against histone deacetylase (HDAC) enzymes have become an important therapeutic tool in oncology; consequently, scientific efforts have fortified the quest for newer and novel HDACi, which forces the design of structurally innovative HDACi. Various urea containing compounds exhibited admirable anticancer activity. On the basis of these observations, we design and synthesize HDAC specific blocker molecules which are specifically besieged towards class I, class II, and class IV HDAC isoforms to enhance the structural assortment for HDACi. Through docking experiments, we identified that the compounds were tightly bound to the isoforms of the HDAC enzymes at their receptor regions. These derivatives potently inhibited the different isoforms, namely, class I, II, and IV of HDACs, by hyperacetylation of lysine residues in A549 cells. The mechanism of apoptosis is evident, regulating tumor suppressor genes and proteins, thereby facilitating the activation of the death receptor pathway by the tumor necrosis factor (TNF) receptor. These derivative facilitated the induction of reactive oxygen species (ROS) generation leading to downregulation of Bcl 2 , and upregulation of Bax expression, thereby dysregulating mitochondrial membrane potential (ΔΨ m ) to release cytochrome c, and activation of intrinsic pathway. These compounds downregulate the extracellular signal‐regulated kinase/mitogen‐activated protein kinase (ERK/MAPK) pathway to inhibit cell growth, proliferation, and metastasis through the matrix metalloproteinases (MMPs) MMP2 and MMP9 in A549 cells. These results suggest that our designed urea based derivatives act as epigenetic targeting agents through HDAC inhibition.
机译：组蛋白脱乙酰酶抑制剂(HDACi)是一个小的分子化学疗法这一目标通过调节染色质重塑组蛋白和非组蛋白的蛋白质。针对组蛋白脱乙酰酶抑制剂酶(HDAC)已成为一个重要的肿瘤治疗的工具;科学的努力追求更新和小说HDACi力量的设计结构创新HDACi。包含化合物表现出令人钦佩的抗癌活性。观察,我们设计和合成HDAC具体的拦截器分子特别围攻向一级,二级和四级HDAC亚型增强结构HDACi分类。实验中,我们发现,化合物被紧密地绑定到的亚型HDAC吗酶的受体区域。衍生品强有力地抑制不同亚型,即类I, II, hdac IV,由hyperacetylation A549的赖氨酸残基细胞。调节肿瘤抑制基因和蛋白质,从而促进活化的死亡肿瘤坏死因子受体途径(肿瘤坏死因子)受体。诱导的活性氧(ROS)一代的差别导致对这些基因Bcl 2,和伯灵顿upregulation表达式,从而就是说,线粒体膜电位(ΔΨm)释放细胞色素c,和激活的内在途径。表达下调细胞外信号调节激酶/促分裂原活化蛋白激酶(ERK / MAPK)途径抑制细胞生长,扩散和转移矩阵金属蛋白酶(mmp) MMP2和MMP9在A549细胞。尿素为基础衍生品作为表观遗传针对代理通过HDAC抑制。

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