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.     

大尺寸电阻加热式碳化硅晶体生长热场设计与优化

大尺寸低缺陷碳化硅(SiC)单晶体是功率器件和射频(RF)器件的重要基础材料,物理气相传输(physical vapor transport, PVT)法是目前生长大尺寸SiC单晶体的主要方法。获得大尺寸高品质晶体的核心是通过调节组分、温度、压力实现气相组分在晶体生长界面均匀定向结晶,同时尽可能减小晶体的热应力。本文对电阻加热式8英寸(1英寸=2.54 cm)碳化硅大尺寸晶体生长系统展开热场设计研究。首先建立描述碳化硅原料受热分解热质输运及其多孔结构演变、系统热输运的物理和数学模型,进而使用数值模拟方法研究加热器位置、加热器功率和辐射孔径对温度分布的影响及其规律,并优化热场结构。数值模拟结果显示,通过优化散热孔形状、保温棉的结构等设计参数,电阻加热式大尺寸晶体生长系统在晶锭厚度变化、多孔介质原料消耗的情况下均能达到较低的晶体横向温度梯度和较高的纵向温度梯度。     

A branch-and-bound method for the minimum k−enclosing ball problem

The minimum k-enclosing ball problem seeks the ball with smallest radius that contains at least k of m given points. This problem is NP-hard. We present a branch-and-bound algorithm on the tree of the subsets of k points to solve this problem. Our method is able to solve the problem exactly in a short amount of time for small and medium sized datasets.     

Molecular design of ambipolar redox-active molecules II: closed-shell systems

This mini-review highlights key structural features that should be taken into account when creating ambipolar redox-active closed-shell metal-free molecules. This type of compound is strongly required for the fabrication of all-organic ‘poleless’ batteries and semiconductors. The suggested strategies aimed at stabilization of both oxidized (cationic) and reduced (anionic) redox-states are based on the comprehensive analysis of the most successful structures taken from the recent publications.     

Response surface methodology toward the optimization of high-energy carotenoid extraction from Aristeus antennatus shrimp

High-energy assisted extraction techniques, like ultrasound assisted extraction (UAE) and microwave assisted extraction (MAE), are widely applied over the last years for the recovery of bioactive compounds such as carotenoids, antioxidants and phenols from foods, animals and herbal natural sources. Especially for the case of xanthophylls, the main carotenoid group of crustaceans, they can be extracted in a rapid and quantitative way with the use of UAE and MAE.     

Generalized Jacobi spectral Galerkin method for fractional pantograph differential equation

This work is concerned with the extension of the Jacobi spectral Galerkin method to a class of nonlinear fractional pantograph differential equations. First, the fractional differential equation is converted to a nonlinear Volterra integral equation with weakly singular kernel. Second, we analyze the existence and uniqueness of solutions for the obtained integral equation. Then, the Galerkin method is used for solving the equivalent integral equation. The error estimates for the proposed method are also investigated. Finally, illustrative examples are presented to confirm our theoretical analysis.     

Pure tetrahedral quadruple systems with index two

An oriented tetrahedron defined on four vertices is a set of four cyclic triples with the property that any ordered pair of vertices is contained in exactly one of the cyclic triples. A tetrahedral quadruple system of order $n$ with index $\lambda$, denoted by ${\text{TQS}}_{\lambda }\left(n\right)$, is a pair $\left(X,\mathrm{?}\right)$, where $X$ is an $n$‐set and $\mathrm{?}$ is a set of oriented tetrahedra (blocks) such that every cyclic triple on $X$ is contained in exactly $\lambda$ members of $\mathrm{?}$. A ${\text{TQS}}_{\lambda }\left(n\right)$ is pure if there do not exist two blocks with the same vertex set. When $\lambda =1$, the spectrum of a pure TQS $\left(n\right)$ has been completely determined by Ji. In this paper, we show that there exists a pure ${\text{TQS}}_2\left(n\right)$ if and only if $n\equiv 1,2\left(\mathrm{mod}3\right)$ and $n\ge 7$. A corollary is that a simple ${\text{QS}}_4\left(n\right)$ also exists if and only if $n\equiv 1,2\left(\mathrm{mod}3\right)$ and $n\ge 7$.     

一种新的岩石非线性黏弹塑性蠕变模型研究

为了克服传统元件组合模型不能描述岩石蠕变过程中非线性特征的缺陷，首先根据加速蠕变阶段的应变和应变率随蠕变时间急剧增大的特点，建立黏塑性应变与蠕变时间的指数函数关系并提出非线性黏塑性体．将该非线性黏塑性体与广义Burgers蠕变模型串联，建立可以描述岩石全蠕变过程的非线性黏弹塑性蠕变模型，根据叠加原理得到一维应力状态下的轴向蠕变方程．然后基于塑性力学理论指出岩石三维蠕变本构方程建立过程中的不足之处，并给出非线性黏弹塑性蠕变模型合理的三维蠕变方程．最后采用不同应力水平下砂岩轴向蠕变试验对模型合理性进行验证，结果表明：拟合曲线与试验曲线吻合度较高，所建蠕变模型能够很好地描述砂岩在不同应力水平下的蠕变变形规律，尤其对加速蠕变阶段的非线性特征描述效果很好，验证了模型的合理性．     

D3h‐Symmetric Porphyrin‐Based Rigid Macrocyclic Ligands for Multicofacial Multinuclear Complexes in a One‐Nanometer‐Sized Cavity

The one‐step synthesis of D_3h‐symmetric cyclic porphyrin trimers 1 composed of three 2,2′‐[4,4′‐bis(methoxycarbonyl)]bipyridyl moieties and three porphyrinatozinc moieties was achieved from a nickel‐mediated reductive coupling of meso‐5,15‐bis(6‐chloro‐4‐methoxycarbonylpyrid‐2‐yl)porphyrinatozinc. Although cyclic trimers 1 were obtained as a mixture that included other cyclic and acyclic porphyrin oligomers, an extremely specific separation was observed only for cyclic trimers 1 when using columns of silica gel modified with pyrenylethyl, cyanopropyl, and other groups. Structural analysis of cyclic trimers 1 was carried out by means of NMR spectroscopy and X‐ray crystallography. Treatment of an η³‐allylpalladium complex with a cyclic trimer gave a tris(palladium) complex containing three η³‐allylpalladium groups inside the space, which indicated that the bipyridyl moieties inside the ring could work as bidentate metalloligands.