2. Academic Validation
  3. Scaffold hopping of celastrol provides derivatives containing pepper ring, pyrazine and oxazole substructures as potent autophagy inducers against breast cancer cell line MCF-7

Scaffold hopping of celastrol provides derivatives containing pepper ring, pyrazine and oxazole substructures as potent autophagy inducers against breast cancer cell line MCF-7

  • Eur J Med Chem. 2022 Apr 15;234:114254. doi: 10.1016/j.ejmech.2022.114254.
Yao Feng 1,  Bing Zhang 2,  Jialun Lv 2,  Peng Zhang 2,  Qing Mao 2,  Fengwei Lin 2,  Jiaxing Zhao 2,  Xuefeng Fu 2,  Yajun Yang 3,  Zhaolin Li 3,  Lei Zhang 4,  Yanhua Mou 5,  Shaojie Wang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang, 110016, China; Ningxia Kangya Pharmaceutical Co., Ltd., Yinchuan, 750000, China.
  • 2 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang, 110016, China.
  • 3 Ningxia Kangya Pharmaceutical Co., Ltd., Yinchuan, 750000, China.
  • 4 Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110016, China. Electronic address: Zhang.Lei@sj-hospital.org.
  • 5 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang, 110016, China. Electronic address: mu_hua_jj@sina.com.
  • 6 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang, 110016, China. Electronic address: wangshaojie@syphu.edu.cn.
PMID: 35290844 DOI: 10.1016/j.ejmech.2022.114254
Abstract

Three series of celastrol derivatives, namely, 6a-6i, 11a-11i and 15a-15i, were designed based on the scaffold hopping strategy. The derivatives were synthesized and biologically evaluated against five human tumor cell lines (i.e. A549, MCF-7, Bel7402, HT-29 and PC3) using MTT assay in vitro. Results showed that compound 11i exhibited apparent antiproliferative activity against the MCF-7 cell line with an IC50 value of 1.31 μM and could remarkably inhibit the colony formation of the MCF-7 cells. Transmission electron microscopy assay, monodansylcadaverine incorporation assay and the expression of LC3 A/B, p62 and Beclin-1 in MCF-7 cells suggested that the potent antiproliferative activity of compound 11i was mainly due to its autophagy-inducing effect. Moreover, compound 11i could arrest the MCF-7 cells in the G2/M phase by regulating the cell-cycle-related proteins Cdk-1 and Cyclin B1. In the zebrafish xenograft model, compound 11i could obviously inhibit the proliferation of the MCF-7 cells. Thus, compound 11i could serve as a promising lead compound for breast Cancer therapy.

Keywords

Autophagy; Celastrol; MCF-7; Scaffold hopping.

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