文献类型：期刊文献

英文题名：Design and linkage optimization of ursane-thalidomide-based PROTACs and identification of their targeted-degradation properties to MDM2 protein

作者：Qi, Zhiwen[1] Yang, Guliang[2] Deng, Tao[4,5] Wang, Jianmin[6] Zhou, Hao[1] Popov, Sergey A.[3] Shults, Elvira E.[3] Wang, Chengzhang[1]

第一作者：齐志文

通信作者：Qi, ZW[1];Wang, CZ[1];Yang, GL[2]

机构：[1]Chinese Acad Forest, Inst Chem Ind Forest Prod, Nanjing 210042, Jiangsu, Peoples R China;[2]Cent South Univ Forestry & Technol, Food Sci & Engn Coll, Natl Engn Lab Rice & By Prod Proc, Changsha 410004, Hunan, Peoples R China;[3]Novosibirsk Inst Organ Chem, Acad Lavrentyev Ave 9, Novosibirsk 630090, Russia;[4]Guangzhou Univ Chinese Med, Inst Trop Med, Guangzhou 501405, Peoples R China;[5]Guangzhou Univ Chinese Med, Sci & Technol Innovat Ctr, Guangzhou 501405, Peoples R China;[6]Hunan Univ, Sch Comp Sci & Engn, Changsha 410012, Peoples R China

年份：2021

卷号：111

外文期刊名：BIOORGANIC CHEMISTRY

收录：;Scopus(收录号：2-s2.0-85104364360);WOS:【SCI-EXPANDED(收录号:WOS:000656969600007)】；

基金：We thank the National Nonprofit Institute Research Grant of CAFINT, China (No. CAFYBB2018GA001) and the Research Foundation of Hunan Education Bureau of China (No. 19A13) for financial support.

语种：英文

外文关键词：Ursolic; PROTAC; MDM2; Thalidomide; Antitumor

摘要：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 IC50 value of 0.23 similar to 0.39 mu M 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.