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
  • 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: [email protected].
  • 5. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang, 110016, China. Electronic address: [email protected].
  • 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: [email protected].
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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