不同性别黄鳝六种组织中LDH同工酶电泳谱的初步研究

本文报告了运用聚丙烯酰胺凝胶圆盘电泳研究不同性别黄鳝的血清、心肌、骨骼肌、肝、肾和生殖腺等六种组织器官中ＬＤＨ同工酶。结果表明六种不同组织中ＬＤＨ同工酶谱各不相同,具有明显的组织特异性。在不同性别中某些同一种组织的ＬＤＨ同工酶谱也发生变化,这说明决定黄鳝ＬＤＨ同工酶表达的因素在不同性别中有差异。     

Design,synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and β-secretase

To explore novel effective drugs for the treatment of Alzheimer’s disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and β-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC₅₀ = 0.567 μM; AChE: IC₅₀ = 1.83 μM), and also showed excellent inhibitory effects on Aβ production of APP transfected HEK293 cells (IC₅₀ = 98.7 nM) and mild protective effect against hydrogen peroxide (H₂O₂)-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Aβ_1–40 production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.     

Design, synthesis, and evaluation of Leu*Ala hydroxyethylene-based non-peptide beta-secretase (BACE) inhibitors

With the aim of developing small molecular non-peptide beta-secretase (BACE) inhibitors, Leu*Ala hydroxyethylene (HE) was investigated as a scaffold to design and synthesize a series of compounds. Taking advantage of efficient combinatorial synthesis approaches and molecular modeling, extensive structure-activity relationship (SAR) studies were carried out on the N- and C-terminal residues of the Leu*Ala HE scaffold. Isobutyl amine was found to be an optimal C-cap, and suitable hydroxylalkylamines at the 3-position and nitro or methyl(methylsulfonyl)amine at the 5-position of isophthalamide as the N-terminus could form additional hydrogen bonds with BACE active sites and help improve potency. Many new potent non-peptide BACE inhibitors were identified in this study. Among them, compounds 37 and 44 exhibited excellent enzyme-inhibiting potency, comparable to that of OM99-2, and obvious inhibitory effects in cell-based assay with low molecular weights (<600).     

CCLab--a multi-objective genetic algorithm based combinatorial library design software and an application for histone deacetylase inhibitor design

The introduction of the multi-objective optimization has dramatically changed the virtual combinatorial library design, which can consider many objectives simultaneously, such as synthesis cost and drug-likeness, thus may increase positive rates of biological active compounds. Here we described a software called CCLab (Combinatorial Chemistry Laboratory) for combinatorial library design based on the multi-objective genetic algorithm. Tests of the convergence ability and the ratio to re-take the building blocks in the reference library were conducted to assess the software in silico, and then it was applied to a real case of designing a 5×6 HDAC inhibitor library. Sixteen compounds in the resulted library were synthesized, and the histone deactetylase (HDAC) enzymatic assays proved that 14 compounds showed inhibitory ratios more than 50% against tested 3 HDAC enzymes at concentration of 20 μg/mL, with IC(50) values of 3 compounds comparable to SAHA. These results demonstrated that the CCLab software could enhance the hit rates of the designed library and would be beneficial for medicinal chemists to design focused library in drug development (the software can be downloaded at: http://202.127.30.184:8080/drugdesign.html).     

Aromatic β-amino-ketone derivatives as novel selective non-steroidal progesterone receptor antagonists

A novel class of non-steroidal progesterone receptor antagonists with aromatic β-amino-ketone scaffold have been synthesized and characterized with high binding affinity and great selectivity for the cognate receptors. Among them, compound 22 was shown to be the most potent progesterone receptor antagonist in cotransfection assay and a murine model of ligand-induced decidualization.     

新疆6个大果红枣裂果性差异及其内在原因分析

该研究以新疆栽培的6个大果型红枣品种(‘骏枣’、‘赞新大枣’、‘金谷大枣’、‘蛤蟆枣’、‘晋赞大枣’、‘新郑大马牙’)全红期果实为对象,通过考察裂果性差异,观察果皮组织结构,测定细胞壁成分及代谢相关酶活性,分析扩展蛋白基因表达的变化,探讨造成枣品种裂果差异的内在规律,为栽培引种及抗裂品种选育提供理论基础。结果表明:(1)‘骏枣’、‘赞新大枣’、‘金谷大枣’属于易裂果品种,而‘蛤蟆枣’、‘晋赞大枣’、‘新郑大马牙’的抗裂果能力较强。(2)6个品种之间的果实角质层厚度差异显著,并以‘晋赞大枣’、‘蛤蟆枣’和‘新郑大马牙’较大;表皮层厚度在品种之间无显著差异;品种间的果肉空腔与果肉面积比例差异显著,由低到高依次为‘蛤蟆枣’‘新郑大马牙’‘晋赞大枣’‘骏枣’‘金谷大枣’‘赞新大枣’。(3)6个品种间果皮的纤维素含量、纤维素酶活性以及原果胶含量、可溶性果胶含量、果胶酶活性等指标均存在显著差异,且原果胶含量与裂果率具有相关性,抗裂品种‘晋赞大枣’和‘蛤蟆枣’的原果胶含量明显低于其他品种;其他指标与它们各自的裂果率未发现相关性。(4)扩展蛋白基因ZjEXP11和ZjEXP12在6个品种果皮中的表达水平差异显著,且与裂果率具有相关关系,并以抗裂果能力较强品种的表达量显著较低。研究发现,新疆大果型红枣的裂果性在品种间存在显著差异,抗裂果品种比易裂果品种具有更厚的角质层和表皮层,以及更小的果肉空腔面积、更低的原果胶含量和更低的扩展蛋白基因ZjEXP11、ZjEXP12表达水平。