Het(aryl)isatin to het(aryl)aminoindoline scaffold hopping: A route to selective inhibitors of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression. A variety of chemical classes have been explored for targeting individual MMP isoforms. In the present study, we further developed our isatin based scaffold BB0223107 capable of binding to and inactivating MMP-2 in a zinc-independent manner (Agamennone et al., 2016). Forty four new compounds were synthesized based on the modified BB0223107. All compounds were tested in enzyme inhibition assays against MMP-2, ?8 and ?13. SAR studies demonstrated that 5-het(aryl)-3-aminoindolin-2-ones (37–39) were active toward MMP-2 and MMP-13. The most potent compounds 33 and 37 displayed an IC₅₀ of 3 µM against MMP-13 and showed a negligible activity toward MMP-8; almost all new compounds were inactive toward MMP-8. Replacement of the isatin ring with a biaryl system (compound 33) did not decrease the potency against MMP-13 but reduced the selectivity. Structure-based computational studies were carried out to rationalize the inhibitory activity data. The analysis of binding geometries confirmed that all fragments occupied the S1′ site in the three enzymes while no ligand was able to bind the catalytic zinc ion. To the best of our knowledge, this is the first example of 3-aminoindolin-2-one-based MMP inhibitors that, based on the computer modeling study, do not coordinate the zinc ion. Thus, the het(aryl)-3-aminoindolin-2-one derivatives emerge as a drug-like and promising chemotype that, along with the hetaryl variations, represents an alternative and thrifty tool for chemical space exploration aimed at MMP inhibitor design.     

Unlocking the Drug Potential of the Bryostatin Family: Recent Advances in Product Synthesis and Biomedical Applications

Bryostatins are a class of naturally occurring macrocyclic lactones with a unique fast developing portfolio of clinical applications, including treatment of AIDS, Alzheimer's disease, and cancer. This comprehensive account summarizes the recent progress (2014–present) in the development of bryostatins, including their total synthesis and biomedical applications. An emphasis is placed on the discussion of bryostatin 1 , the most-studied analogue to date. This review highlights the synthetic and biological challenges of bryostatins and provides an outlook on their future development.     

关于高师院校计算机专业教学改革的几点建议

本文以高等师范院校计算机专业教学改革为例,从教育观念的更新、教学模式的转变、教学手段的更新、教学对象的再认识、教学中的教材教法等多个方面分析以网络为主的现代教育模式改革的思想,目的在于探索出一条以多媒体和网络为主体的教学环境下的教育新思路。     

固体力学有限元体系的结构拓扑变化理论

本文是文[1]的继续.文[1]提出了杆件系统的结构拓扑变化理论和拓扑变化法本文将这一理论和方法推进到连续体有限元体系;且在此基础上揭示出有限元体系的一个新性质,称为基本位移之梯度的正交性定理,从而给出一套设计敏度的显式表达式,可直接用于计算.     

Surface structures formed by individual adsorption and coadsorption of Mn and Bi on Cu(0 0 1), studied by LEED

We have studied the individual adsorption of Mn and Bi, and their coadsorption on Cu(0 0 1) by low-energy electron diffraction (LEED). For Mn, we have determined the c(2 × 2) structure formed at 300 K, whose structure had been determined by several methods. We reconfirmed by a tensor LEED analysis that it is a substitutional structure and that a previously reported large corrugation (0.30 Å) between substitutional Mn and remaining surface Cu atoms coincides perfectly with the present value. In the individual adsorption of Bi, we have found a c(4 × 2) structure, which is formed by cooling below ∼250 K a surface prepared by Bi deposition of ∼0.25 ML coverage at 300 K where streaky half-order LEED spots appear. The c(4 × 2) structure has been determined by the tensor LEED analysis at 130 K and it is a substitutional structure. In the coadsorption, we found a c(6 × 4) structure, which has been determined by the tensor LEED analysis. It is very similar to the previously determined structure of the c(6 × 4) formed by coadsorption of Mg and Bi, and embedded MnBi₄ clusters are arranged in the top Cu layer instead of MgBi₄. Large lateral displacements of Bi atoms in the c(6 × 4)-(Mn + Bi) suggest that the Mn atoms undergo the size-enhancement caused by their large magnetic moment.     

红胫平顶蝗(直翅目:蝗总科:斑翅蝗科)雌性的发现

红胫平顶蝗(Flatovertex rufotibialis Zheng)的雄性为郑哲民先生1981年所记述的新种,标本采自云南昆明,当时未采到雌性.对我国斑翅蝗科昆虫进行研究,在整理采自云南大理(点苍山)的蝗虫标本时,发现有该种雌性一头,本文将雌性特征进行描述.     

行波型热声发动机的分布参数法热力分析

在现有热声网络模型的基础上 ,对行波型热声发动机采用分布参数法进行了详细地分析 ,得到了较为完整的分布参数法网络模型 ,并给出了该模型的定性关系式 ,所得结果与采用集总参数法的结果有很大差异。分析表明 ,分布参数法更适合于一般的系统情况 ,集总参数法仅仅在一定条件下才适用。文中对一个实际系统应用分布参数法进行了分析 ,得到一些结论 ,对于我们设计行波型热声发动机有非常重要的理论指导意义