Tetracyanoresorcin[4]arene selectively recognises trimethyllysine and inhibits its enzyme-catalysed demethylation

Abstract

Nε-methylation of lysine within proteins is a critical biological process that, among other roles, is involved in the control of gene expression. Compounds that recognise Nε-methylated lysine may therefore be useful probes for the study of the associated biological mechanisms and have therapeutic potential. Here, we show that tetracyanoresorcin[4]arene (1) selectively recognises Nε-trimethyllysine and binds to Nε-trimethyllysine within the context of a short peptide. Its binding properties compare favourably to a previously characterised Nε-trimethyllysine binder, p-sulfonatocalix[4]arene (2). We also show that both 1 and 2 inhibit the demethylation of Nε-trimethyllysine within a histone-derived peptide by the histone demethylase KDM4A.     

Epigenetic Modifications Induced by Olive Oil and Its Phenolic Compounds: A Systematic Review

Many studies demonstrated that olive oil (especially extra virgin olive oil: EVOO) phenolic compounds are bioactive molecules with anti-cancer, anti-inflammatory, anti-aging and neuroprotective activities. These effects have been recently attributed to the ability of these compounds to induce epigenetics modifications such as miRNAs expression, DNA methylation and histone modifications. In this study, we systematically review and discuss, following the PRISMA statements, the epigenetic modifications induced by EVOO and its phenols in different experimental systems. At the end of literature search through “PubMed”, “Web of Science” and “Scopus”, 43 studies were selected.Among them, 22 studies reported data on miRNAs, 15 on DNA methylation and 13 on histone modification. Most of the “epigenomic” changes observed in response to olive oil phenols’ exposure were mechanistically associated with the cancer preventive and anti-inflammatory effects. In many cases, the epigenetics effects regarding the DNA methylation were demonstrated for olive oil but without any indication regarding the presence or not of phenols. Overall, the findings of the present systematic review may have important implications for understanding the epigenetic mechanisms behind the health effects of olive oil. However, generally no direct evidence was provided for the causal relationships between epigenetics modification and EVOO health related effects. Further studies are necessary to demonstrate the real physiological consequences of the epigenetics modification induced by EVOO and its phenolic compounds.     

Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 methyltransferase activity

We described herein structure-based design,synthesis and evaluation of conformationally constrained,cyclic peptidomimetics to block the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 histone methyltransferase activity.Our study has yielded cyclic peptidomimetics with very high binding affinities to WDR5(Kivalues 1 nmol/L) and function as antagonists of the MLL1 histone methyltransferase activity.     

A Photoactivatable Platinum(IV) Complex Targeting Genomic DNA and Histone Deacetylases

We report toxic effects of a photoactivatable platinum(IV) complex conjugated with suberoyl‐bis‐hydroxamic acid in tumor cells. The conjugate exerts, after photoactivation, two functions: activity as both a platinum(II) anticancer drug and histone deacetylase (HDAC) inhibitor in cancer cells. This approach relies on the use of a Pt^IV pro‐drug, acting by two independent mechanisms of biological action in a cooperative manner, which can be selectively photoactivated to a cytotoxic species in and around a tumor, thereby increasing selectivity towards cancer cells. These results suggest that this strategy is a valuable route to design new platinum agents with higher efficacy for photodynamic anticancer chemotherapy.     

环肽类组蛋白去乙酰化酶抑制剂

组蛋白去乙酰化酶抑制剂是一类以组蛋白去乙酰化酶为靶点的新型靶向抗肿瘤药物,在抗增殖、促凋亡、促分化、阻滞细胞生长周期、抗血管生成等方面有很好的作用。组蛋白去乙酰化酶抑制剂以其独特的抗肿瘤作用机理,在研发肿瘤治疗药物中占有重要地位。在组蛋白去乙酰化酶抑制剂分类中,环肽类抑制剂结构最为复杂,对多种类型的实体瘤及血液学癌细胞均具有良好的对抗作用。本文针对天然和化学合成的环肽类组蛋白去乙酰化酶抑制剂中金属结合区、表面识别区以及连接区的结构特点进行了综述,并描述了各类抑制剂对酶的抑制活性和抗肿瘤增殖活性。对抑制剂不同结构区的修饰、改造可以使抑制剂对不同肿瘤细胞具有高效性和特异性作用,通过构效关系研究寻找具有高效低毒、靶向性环肽类抑制剂的结构规律,可为研究开发抗肿瘤药物提供帮助。     

表观遗传学研究进展

 概述了表观遗传调节模式、表观遗传调节的效应、植物表观遗传学的研究进展等。在每种细胞中,都会发生一部分特异基因激活、另一部分基因抑制的现象,形成多种基因表达模式。表观遗传指DNA序列不发生变化,而基因表达发生可遗传改变的现象。表观遗传学改变包括DNA甲基化、组蛋白修饰、非编码RNA作用等,产生基因组印记、母性影响、基因沉默、核仁显性、休眠转座子激活等效应。表观遗传变异是环境因素和细胞内遗传物质间交互作用的结果,其效应通过调节基因表达,控制生物学表型来实现。正是因为表观修饰对于维持生物体内环境和各器官系统功能的重要性,表观遗传的异常会引发疾病,这也成为药物和治疗方案设计的着眼点。     

组蛋白乙酰化的耦合增强拉曼散射生物传感方法

提出了一种组蛋白乙酰化修饰检测的耦合增强拉曼散射生物传感新方法. 该方法以金纳米粒子为表面增强拉曼散射(SERS)基底, 表面修饰乙酰化组蛋白H3多肽为识别探针, 对甲氧基苯硫酚(4-MTP)为拉曼标记物, 制备了组蛋白乙酰化修饰检测的SERS纳米探针. 通过紫外可见吸收光谱与动态光散射分析, 证实了组蛋白乙酰化抗体可介导SERS纳米粒子发生可控组装与聚集, 使SERS纳米探针间发生局域电场共振耦合, 产生显著增强的SERS信号. 基于此, 通过待测抗原与SERS纳米探针对抗体的竞争性相互作用, 我们设计了组蛋白乙酰化修饰检测的竞争免疫SERS生物传感方法. 该法操作简便、快速、重现性好, 且裸眼即能进行可视化鉴定. 通过设计不同染料标记的SERS纳米探针, 该法有望实现多种组蛋白修饰的复合检测.     

Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5′′‐epi‐Spiruchostatin B,FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity

The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5′′‐epi‐spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia–Kocienski olefination of a 1,3‐propanediol‐derived sulfone and a L ‐ or D ‐malic acid‐derived aldehyde to access the most synthetically challenging unit, (3S or 3R,4E)‐3‐hydroxy‐7‐mercaptohept‐4‐enoic acid, present in a D ‐alanine‐ or D ‐valine‐containing segment; ii) a condensation of a D ‐valine‐D ‐cysteine‐ or D ‐allo‐isoleucine‐D ‐cysteine‐containing segment with a D ‐alanine‐ or D ‐valine‐containing segment to directly assemble the corresponding seco‐acids; and iii) a macrocyclization of a seco‐acid using the Shiina method or the Mitsunobu method to construct the requisite 15‐ or 16‐membered macrolactone. The present synthesis has established the C5′′ stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell‐growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure–activity relationships. It was also found that unnatural 5′′‐epi‐spiruchostatin B shows extremely high selectivity (ca. 1600‐fold) for class I HDAC1 (IC₅₀=2.4 nM ) over class II HDAC6 (IC₅₀=3900 nM ) with potent cell‐growth‐inhibitory activity at nanomolar levels of IC₅₀ values.     

新型苯甲酰胺类HDAC抑制剂的合成及其抗肿瘤活性

以MS-275为先导化合物,设计并合成了7个新型苯甲酰胺类化合物（6a~6c, 14a, 14b, 15a和18）,其结构经¹H NMR和ESI-MS表征。采用MTT法测定了6a~6c, 14a, 14b, 15a和18对人急性白血病细胞(HL60)和人乳腺癌细胞(MCF-7)的体外抗肿瘤细胞增殖活性。结果表明：N-(2-氨基苯)-3-［4-(吡啶-3-基)嘧啶-2-氨基］己酰胺（6a）, N-(2-氨基苯)-4-【3-{4-［(二乙胺基)甲基］苯基}丙烯酰】苯甲酰胺（14a）和N-(2-氨基苯)-4-［3-(吡啶-3-基)丙烯酰］丙酰胺(18）的抑制活性较好,其GI₅₀依次为5.72 μmol·L^-1, 6.91 μmol·L^-1, 7.11 μmol·L^-1和3.46 μmol·L^-1, 4.12 μmol·L^-1, 3.97 μmol·L^-1,优于MS-275(7.88 μmol·L^-1和4.49 μmol·L^-1)。