Intracellular effects of prodrug-like wortmannin probes  

作　　者：Shasha Ying Shubo Du Jia Dong Bi Xuan Ng Chengwu Zhang Lin Li Jingyan Ge Qing Zhua 

机构地区：[1]Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology [2]Department of Chemistry, National University of Singapore [3]Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (Nanjing Tech)

出　　处：《Chinese Chemical Letters》2019年第1期67-70,共4页中国化学快报（英文版）

基　　金：financially supported by the Natural Science Foundation of Zhejiang Province (Nos. LQ16B020003, LY17B060009);the National Natural Science Foundation of China (Nos. 21708034, 21472172, 81672508, 61505076);Jiangsu Provincial Foundation for Distinguished Young Scholars (No. BK20170041)

摘　　要：Wortmannin, a known inhibitor of phosphoinositide 3-kinases(PI3 Ks), their low selectivity and high toxicity is still problematic and less is known about their effects on PI3 Ks in cellular systems. Hence, we have synthesized a series of multifunctional wortmannin probes with the ability to self-activate, by installing a clickable handle at C11 site, and secondary amine and cancer-targeting moiety at C20 site respectively. MTT assay first confirmed that self-activating probes have better inhibition potency and biotin enhanced their cancer cell uptake. Further experiments showed most of probes can target PI3 K/Akt/mTOR pathway with prolonged turn-over time. Protein profiling and pull-down results were observed that the derivatives not only labelled four PI3 Ks with selectivity, but also engaged in covalent interactions with numerous cellular proteins which could be the major reason of their high toxicity.Wortmannin, a known inhibitor of phosphoinositide 3-kinases(PI3Ks), their low selectivity and high toxicity is still problematic and less is known about their effects on PI3Ks in cellular systems. Hence, we have synthesized a series of multifunctional wortmannin probes with the ability to self-activate, by installing a clickable handle at C11 site, and secondary amine and cancer-targeting moiety at C20 site respectively. MTT assay first confirmed that self-activating probes have better inhibition potency and biotin enhanced their cancer cell uptake. Further experiments showed most of probes can target PI3K/Akt/mTOR pathway with prolonged turn-over time. Protein profiling and pull-down results were observed that the derivatives not only labelled four PI3Ks with selectivity, but also engaged in covalent interactions with numerous cellular proteins which could be the major reason of their high toxicity.

关 键 词：WORTMANNIN P3IK Activity-based probe PROFILING Cancer-targeting Self-activating 

分 类 号：O6[理学—化学]