Selective synthesis of A-ring Е-arylidene derivatives from ß-sitosterol and their activity.

A series of 24-ethylcholest-4-ene-3,6-dione 2E-arylidene-derivatives has been synthesized by a Claisen-Schmidt reaction from a natural phytosterol ß-sitosterol with yields of 80-85%. The structure of the obtained compounds was confirmed by NMR spectroscopy, including two-dimensional correlation experiments. The synthesized compounds were evaluated for their in vitro cytotoxicity and α-glucosidase inhibitory activity. It was established that compound 3 with pyridin-3-ylmethylene moiety exhibited a selective cytotoxic effect against the U251 cancer cell line with 99.31% inhibition of cancer cell growth. Compounds with pyridin-4-ylmethylene 4 and furan-2-ylmethylene-5 fragments were the most active inhibitors of α-glucosidase with IC50 64.00 and 38.95 µM, being 3- and 5-times more active than acarbose. Binding mode to α-glucosidase and ADMET characteristics for the lead molecule 5 were proposed computationally. To sum up, an efficient approach to the derivatives with promising antidiabetic activity based on available natural product ß-sitosterol is suggested.

Spatial heterogeneous distribution of SiO(x) → SiO(x±1) reactions in silica liquid.

We have numerically studied the diffusion mechanism in silica liquid following an approach where the diffusion rate is evaluated via the SiO(x) → SiO(x±1) reaction rate υ(react) and the mean square displacement of particles d(react) as a reaction happens. Five models at pressure up to 25 GPa and at a temperature of 3000 K have been constructed by molecular dynamic simulation. When applying pressure to the liquid, υ(react) increases monotonously because the Si-O bond becomes weaker with pressure. Meanwhile d(react) attains a maximum near the point of 10 GPa despite the particles move in a significantly smaller volume. Furthermore, the SiO(x) → SiO(x±1) reactions are spatially heterogeneously distributed in the liquid. Upon low pressure, most reactions happen with a small number of Si particles. This reaction localization causes the diffusion anomaly and dynamics heterogeneity in the liquid. With increasing pressure the diffusion mechanism changes from the heterogeneous spatial distribution of reactions to homogeneous one. The simulation also reveals two distinguished regions with quite different coordination environments where the reaction rate significantly differs from each other. These sets of Si particles migrate in space over time and form regions with so-called "fast" and "slow" Si particles. The result obtained here indicates the coexistence of low- and high-density regions, and supports the concept of polymorphism in silica liquid.

Computer simulation of diffusion in silica liquid under temperature and pressure.

We have studied the diffusion mechanism in silica liquid following a new approach where the diffusion rate is estimated via the rate of SiO(x) → SiO(x±1) and the mean square displacement of Si particles per SiO(x) → SiO(x±1). Molecular dynamics simulation has been conducted for a model consisting of 1998 particles over a wide range of temperatures (3000-4500 K) and pressure (from 0 to 25.75 GPa). Our results show that the rate of SiO(x) → SiO(x±1) increases either with increasing the temperature or pressure. Further, we find that SiO(x) → SiO(x±1) is heterogeneously distributed through the network structure of the liquid. In particular, it is concentrated on a small section of Si particles in a low-temperature regime and at ambient pressure. The spatial localisation of SiO(x) → SiO(x±1) originates from the fact that the stable unit in low- and high-pressure regime is SiO4 and SiO6, respectively. The major change in the diffusion mechanism under pressure or temperature concerns the change in the distribution of SiO(x) → SiO(x±1) through the network structure. It is finally shown that the spatial localisation of SiO(x) → SiO(x±1) is responsible for the dynamics heterogeneity and the diffusion anomaly for silica liquid. This finding supports the concept that as the temperature approaches the glass transition point, SiO(x) → SiO(x±1) spatially localises such that the diffusivity drops and the dynamics are anomalously slow.

Correlation effect for dynamics in silica liquid.

We study numerically the diffusion mechanism in silica liquid via molecular dynamics simulation. For this purpose we examine the evolution of structural units SiO(x) (x=4-6) for different times and at temperatures from 3000 to 4500 K. Simulation shows that the diffusivity of the silicon particle is performed through the transition SiO(x)→SiO(x±1), i.e., the bond-breaking and bond-reformation events. As a SiO(x)→SiO(x±1) transition occurs, one oxygen particle moves out of or into the coordination shell, leading to a collective movement of Si particles. Other types of transitions, for instance, SiO(4)→SiO(6) or SiO(6)→SiO(4), are negligible. We establish an expression for the diffusion coefficient that shows that the diffusivity is not proportional to the rate of SiO(x)→SiO(x±1) because it is strongly localized in the network structure. A high degree of localization of SiO(x)→SiO(x±1) leads to a heterogeneous dynamics. We find that the dynamics slowdown is determined by two terms: The first one concerns the change in the statistic property related to the fraction of non-four-coordinated units (SiO(3), SiO(5), SiO(6), and SiO(7)) and the second term concerns the correlation effect. Furthermore, we show that the correlation coefficient depends on both the fraction of the back-forth SiO(x)→SiO(x±1) transition and the degree of localization of SiO(x)→SiO(x±1). Our finding qualitatively supports the ideal that anomalously slow dynamics near the glass-transition point is caused by a strong localization of SiO(x)→SiO(x±1).