Citation: Jun Mu, Xin Xie, Shanshan Xiong, Yuehua Zhang, Yuting Wang, Qian Zhao, Hongping Zhu, Wei Huang, Gu He. Discovery of spirooxindole–ferrocene hybrids as novel MDM2 inhibitors[J]. Chinese Chemical Letters, ;2021, 32(6): 1897-1901. doi: 10.1016/j.cclet.2021.01.033 shu

Discovery of spirooxindole–ferrocene hybrids as novel MDM2 inhibitors

Jun Mu ^{a, 1} ,
Xin Xie ^{b, 1} ,
Shanshan Xiong ^a ,
Yuehua Zhang ^a ,
Yuting Wang ^b ,
Qian Zhao ^b ,
Hongping Zhu ^b ,
Wei Huang ^{b, *,} ,
Gu He ^{a, *,}

a.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
b.
State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China

huangwei@cdutcm.edu.cn

hegu@scu.edu.cn

Received Date: 9 December 2020
Revised Date: 7 January 2021
Accepted Date: 19 January 2021
Available Online: 26 January 2021

Figures(4)

A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis. In vitro protein binding and cellular proliferation assays suggested that compound 5d was the most potent mouse double minute 2 homolog (MDM2) inhibitor. In addition, mechanistic studies indicated that compound 5d suppressed MDM2-mediated p53 degradation, induced apoptosis and promoted oxidative damage. Molecular docking studies have suggested that 5d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53. This work can provide a basis for the development of novel multifunctional MDM2 inhibitors. The further exploration of more derivatives from this library and additional investigation of organocatalysis application in the development of new molecules may generate new potential lead compounds for cancer-targeted therapy.
- Spirooxindole,
- Ferrocene,
- MDM2,
- Apoptosis,
- Breast cancer
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