2. Academic Validation
  3. Design and synthesis of 6,20-epoxy A-ring modified oridonin derivatives with antitumor activity through extrinsic and mitochondrial pathways

Design and synthesis of 6,20-epoxy A-ring modified oridonin derivatives with antitumor activity through extrinsic and mitochondrial pathways

  • Bioorg Chem. 2024 Jul 11:151:107632. doi: 10.1016/j.bioorg.2024.107632.
Haonan Li 1,  Xiaogang Luo 1,  Feilong Zhu 2,  Chao Wang 1,  Jiesen Wang 1,  Siyuan Wang 3,  Huiming Hua 4,  Jincai Lu 5,  Dahong Li 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 3 College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, PR China.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: huimhua@163.com.
  • 5 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: jincailu@126.com.
  • 6 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: lidahong0203@163.com.
PMID: 39003943 DOI: 10.1016/j.bioorg.2024.107632
Abstract

Oridonin is an antitumor ent-kaurane diterpenoid that medicinal chemists have been paying close attention to in recent years. Herein, a novel 6,20-epoxy A-ring modified oridonin derivative 2 was obtained by a 6-step synthesis. A series of 14-O derivatives of 2 (EpskA1-EpskA24) were synthesized to further enhance the activity. Based on their cytotoxicity against MCF-7, A549 and L-02 cells, EpskA9, EpskA10 and EpskA21 were chosen for further screening to obtain a wider antitumor spectrum. Collectively, EpskA21 showed the most potent antiproliferative activity, inhibiting proliferation and migration, and inducing Apoptosis and cell cycle arrest in MCF-7 and MIA-PaCa-2 cells. With the help of network pharmacology analysis, apoptosis-related proteins were selected and further tested by western blot assay. The inhibition of PI3K/Akt and an increase in the levels of Bax/Bcl-2 ratio, Cyt-C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP was observed, indicating that EpskA21 induced Apoptosis through the mitochondrial pathway. Given that an increase in DR5 expression and activated Caspase-8 were also observed, the extrinsic Apoptosis pathway might also be related to the antitumor effect.

Keywords

Antitumor; Apoptosis; Ent-kaurane; Oridonin; Structural modification.

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