Zhiwen Qi,Guliang Yang,Tao Deng,Jianmin Wang,Hao Zhou,Sergey A. Popov,Elvira E. Shults,Chengzhang Wang
Ursolic acid (UA) is an accessible triterpenoid, widely applied in the design and synthesis of antitumor compounds. However, the mechanism of its anti-tumor effect is still unclear. To verify the molecular mechanism of its biological activity, based on the bifunctional activity of ubiquitination and subsequent proteasomal degradation of the target protein of the proteolysis-targeting chimeras (PROTACs) strategy, here we report the design, synthesis and cellular activity of six UA PROTAC hydrochloride compounds 1A - 1F , in which UA acts as the binding ligand of the PROTAC and is linked to thalidomide (E3 ligand) through a series of synthetic linkers. The results revealed that compound 1B , connected with a POE-3 (3-Polyoxyether) possessed remarkable in vitro antitumor activity (with the IC 50 value of 0.23 ~ 0.39 μM against A549, Huh7, HepG2). WB results demonstrated that the administration of compound 1B induced significant degradation of MDM2 (only 25% to that of SM1), and promoted the expression of P21 and PUMA proteins, and thus inhibited the proliferation (77.67% of 1B vs 60.37% of CON in G1 phase) and promoted the apoptosis (26.74% of 1B vs 3.35% of CON) of A549 cells. This work demonstrated proof of designing the efficient target protein degradation by UA PROTACs with the POE linkers. In addition, we confirmed that UA possess the characteristic of targeted-binding the protein of murine double minute-2 protein (MDM2). This will lay a foundation for the comprehensive utilization of forest natural compound UA.
The recovery, exfoliation, and regeneration of nanoparticles are important factors that limit the application of molecularly imprinted catalysts. In this study, a targeted catalytic monolithic membrane, M@MIP, was constructed by a one-step phase-transfer technique to achieve efficient recycling of molecularly imprinted nanoparticles and performance enhancement of the catalytic membrane. The average water flux of M@MIP increases by about 22% compared to polyvinylidene fluoride. The sulfamethoxazole removal ability reached 99% in complex water, demonstrating great promise for excellent targeting and catalytic degradation. The total organic carbon removal extent by M@MIP in actual wastewater was as high as 46%. In addition, the M@MIP showed excellent regeneration, stability (remained above 91% over six repeated cycles) and a significant ability to reduce ecotoxicity. This study offers a new solution for the efficient use and recycling of molecularly imprinted nanoparticles and the efficient removal of low-concentration pollutants.
危险品化学品经营许可证（带存储）