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.     

论中小城市社区建设中的政府职能

我国中小城市社区建设尚处于起步阶段,运行机制不够健全,发展水平不高,体现出政府作用突出,社区自治权利淡化;社区居民参与不足;社区经济薄弱等特征。为此,在中小城市社区建设中,应进一步明确区(县)一级政府对城市的管理职能;建立和培育各类社会中介组织;理性区分政府对城市的行政管理与居民参与的社区自治管理;政府应提供社区公共品供给的制度保证并妥善解决社区发生的"外部性"问题。     

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.     

旅游人类学在中国

旅游业急速发展的现实充当了中国旅游人类学发展最强大的推动力,旅游人类学在国外四十多年的成长也为其提供了良好的基础和借鉴。中国旅游人类学在这双重合力的推动下,学术活动频繁、专业刊物搭建平台、基金资助力度加大、学科建设初见成效。在旅游的社会文化影响、旅游真实性理论、社区参与旅游发展等领域的研究进展显著。但是,仍存在不少问题,既需要深入发掘人类学本身的理论和方法优势,也还要扎根中国现实。     

Neutral Community Theory: How Stochasticity and Dispersal-Limitation Can Explain Species Coexistence

Neutral community theory explains biodiversity, i.e. the coexistence of several species, as the result of a stochastic balance between immigration and extinction on a local level, and between speciation and extinction on a regional level. The most popular model, presented by Hubbell in 2001, has seen many analytical developments in recent years, which can be used in model analysis, model testing and model comparison. We review these developments here, and present alternative derivations and shine previously unnoticed lights on them.     

Future pathways for combinatorial chemistry

Summary Investment in combinatorial chemistry (combichem) in the pharmaceutical industry is being driven by the need for increased efficiency. Results from pioneers in the field have demonstrated where mixture or discrete compound synthesis is useful, and what mixture sizes and compound concentrations are appropriate. To make the techniques of combichem of general utility in drug discovery, a broad range of advances is still required. Conversion of organic chemistry to solid phase conditions is key, as are developments in linkers and resins. Library design methodology requires further development. Combinatorial biosynthesis of focused libraries of natural products holds great promise for capitalising on hardwon natural product leads. Miniaturisation of screens is required to reduce the cost of screening combinatorial libraries. Developments in the processes preceding and following synthesis are required to enable the flow of increased numbers of compounds without new bottlenecks developing. The impact of combinatorial chemistry will be greatly enhanced by synergy with ongoing parallel developments in genetic technologies, screening technologies and bioinformatics.     

罗平布依文化的内涵与价值建构

罗平布依化是我国布依族化的重要组成部分。它既保持着布依整体原生化的优秀内质，又有独特的再生创造话性。其特点是：(1)以美丽的自然环境为裁体；(2)以独特的民俗民趣为形态；(3)以鲜明的民族气质为核心；(4)以丰富的民间艺术形式为见证。强化这些特点，是建构罗平布依化价值的基本思路。“民族尊重”和“宽容姿态”是罗平布依化价值建构的起点和最后归宿。     

重庆主城区社区体育的现状调查

采用问卷调查、文献资料、数理统计等研究方法，对重庆市主城区社区体育现状进行调查，分析了社区居民参加体育活动的内容、时间、地点、形式、规模，以及社区体育的服务管理、设施管理、体育人才管理、体育经营管理系统，并提出了符合实情，可体现地理、环境特点的重庆主城区社区体育发展对策。