Citation: Ying Shasha, Du Shubo, Dong Jia, Ng Bi Xuan, Zhang Chengwu, Li Lin, Ge Jingyan, Zhu Qing. Intracellular effects of prodrug-like wortmannin probes[J]. Chinese Chemical Letters, ;2019, 30(1): 67-70. doi: 10.1016/j.cclet.2018.05.030 shu

Intracellular effects of prodrug-like wortmannin probes

Ying Shasha ^a ,
Du Shubo ^b ,
Dong Jia ^a ,
Ng Bi Xuan ^b ,
Zhang Chengwu ^c ,
Li Lin ^c ,
Ge Jingyan ^a,, ,
Zhu Qing ^a,,

a.
Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China
b.
Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
c.
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), Nanjing 211816, China

Corresponding author: Ge Jingyan, gejy@zjut.edu.cn Zhu Qing, zhuq@zjut.edu.cn
Received Date: 28 March 2018
Revised Date: 15 May 2018
Accepted Date: 16 May 2018
Available Online: 19 January 2018

Figures(3)

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.
- Wortmannin,
- P3IK,
- Activity-based probe profiling,
- Cancer-targeting,
- Self-activating
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