PEGylated Poly-HDACi: A Designer Polyprodrug from Optimized Drug Units**

We designed, synthesized, and characterized a tri-block copolymer. Its hydrophobic part, a chain of histone deacetylase inhibitor (HDACi) prodrug, was symmetrically flanked by two identical PEG blocks, whereas the built-in HDACi was a linear molecule, terminated with a thiol at one end, and a hydroxyl group at the other. Such a feature facilitated end-to-end linkage of prodrugs through alternatively aligned disulfides and carbonates. The disulfides served dual roles: redox sensors of smart nanomedicine, and warheads of masked HDACi drugs. This approach, carefully designed to benefit both control-release and efficacy, is conceptually novel for optimizing drug units in nanomedicine. Micelles from this designer polyprodrug released only PEG, CO₂ and HDACi, and synergized with DOX against HCT116 cells, demonstrating its widespread potential in combination therapy. Our work highlights, for the first time, the unique advantage of thiol-based drug molecules in nanomedicine design.     

HFIP-Promoted de Novo Synthesis of Biologically Relevant Nonnatural α-Arylated Amino Esters and Dipeptide Mimetics

Amino acids are fundamental building blocks, which have been extensively used in drug design and organic synthesis. However, nonnatural amino acids are relatively less studied. In this work, the authors report the first HFIP-promoted de novo synthesis of nonnatural α-arylated amino esters and dipeptide mimetics (27 examples, up to 99 % yield) from readily available amines, ethyl glyoxylate and electron-rich arenes under mild conditions, in which one C−C bond, one C−N bond and one chiral center were established simultaneously. The reaction was also performed on a gram scale, giving compound 4 a in 96 % yield. In addition, this protocol was successfully applied to the late-stage elaboration of drug molecules, such as tranylcypromine (TCP or PCPA) and troxipide. Interestingly, compound 4 h inactivated histone lysine specific demethylase 1 (LSD1) potently with an IC₅₀ value of 0.296 μm . To the best of our knowledge, compound 4 h is the first LSD1 inhibitor derived from nonnatural α-arylated amino esters, and therefore could be used as a hit compound for the development of new LSD1 inhibitors. The synthesized nonnatural α-arylated amino esters and dipeptide mimetics as unique building blocks may have potential synthetic utilities.     

海洋烟曲霉菌产脱乙酰酶发酵条件优化

几丁质酶是一类复合酶,包括脱乙酰酶、几丁质酶、壳聚糖酶、几丁寡糖酶、几丁二糖酶等,将脱乙酰酶应用于壳聚糖的制备中,不仅可以有效地从甲壳素(几丁质)分子中脱除乙酰基,而且不会把甲壳素的长链降解为小分子,可以制备出高脱乙酰度且性能独特的壳聚糖,同时不存在排放废碱液而对环境造成严重污染.     

Gold Nanoparticle Based Fluorescence Resonance Energy Transfer Immunoassay for the Detection of the Histone Deacetylase Activity using a Fluorescent Peptide Probe

A novel platform for detection of histone deacetylase (HDAC) activity has been developed using a gold nanoparticle based fluorescence resonance energy transfer (FRET) immunoassay. This strategy combined the acetylated fluorescent peptide probe with the anti-acetyl antibody functionalized Au NPs to measure the deacetylation activity of histone deacetylase sirtuin2. Enzymatic deacetylation of the acetylated peptide substrate was detected by a gold nanoparticle labeled anti-acetyl peptide antibody with the formation of the immunocomplex resulting in energy transfer between the fluorescent dyes and the nanoparticles. Due to the highly efficient fluorescence quenching of the gold nanoparticles, the proposed method shows a low background and favorable sensitivity. In addition, this approach can be applied to the evaluation of HDAC inhibitor activity. The proposed platform should facilitate the development of new assays for HDAC activity and other histone modifications.     

基于Chlamydocin骨架设计合成环肽类HDACi及其抗肿瘤活性

组蛋白去乙酰化酶(HDACs)通过催化各种底物蛋白包括组蛋白、转录因子、α-微管蛋白和核输入蛋白等的ε-赖氨酸残基乙酰化侧链的去乙酰化来影响细胞功能,抑制HDAC活性可以治疗表观遗传异常引起的癌症和其他慢性疾病.以HDAC抑制剂(HDACi) Chlamydocin为骨架设计合成一类新型抑制剂,将HDACi的结合区设计为二硫键结构、在环肽中苯丙氨酸的苯环不同位点引入甲基,合成4种不同序列的环肽类HDACi.考察HDACi体外抗肿瘤细胞(MCF-7,Hela和7721)活性,结果表明HDACi对三种肿瘤细胞系均显示良好的生长抑制作用,细胞形态都发生明显变化,其中对Hela细胞的毒性最高,IC50达到0.1 μmol/L.     

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.     

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.     

NMR assignments and histone specificity of the ING2 PHD finger

The ING2 plant homeodomain (PHD) finger is recruited to the nucleosome through specific binding to histone H3 trimethylated at lysine 4 (H3K4me3). Here, we describe backbone and side chain assignments of the ING2 PHD finger, analyze its binding to the unmodified and modified histone and p53 peptides, and map the histone H3 and H3K4me3 binding sites based on chemical shift perturbation analysis. Copyright © 2009 John Wiley & Sons, Ltd.