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

• Published in: European journal of medicinal chemistry 2022-04, Vol.234, p.114254-114254, Article 114254
• Main Authors: Feng, Yao, Zhang, Bing, Lv, Jialun, Zhang, Peng, Mao, Qing, Lin, Fengwei, Zhao, Jiaxing, Fu, Xuefeng, Yang, Yajun, Li, Zhaolin, Zhang, Lei, Mou, Yanhua, Wang, Shaojie
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Apoptosis; Autophagy; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Celastrol; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; MCF-7; MCF-7 Cells; Oxazoles - pharmacology; Pentacyclic Triterpenes; Pyrazines - pharmacology; Scaffold hopping; Structure-Activity Relationship; Zebrafish - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114254

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. [Display omitted] •Three series of celastrol derivatives were designed based on the scaffold hopping strategy.•The derivatives were evaluated for their antiproliferative activities.•The structure-activity relationships were investigated.•Compound 11i exhibited remarkable growth inhibition in MCF-7 cells through inducing autophagy.•Compound 11i could inhibit the proliferation of MCF-7 cells in zebrafish xenograft model.