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Design and synthesis of 6,20-epoxy A-ring modified oridonin derivatives with antitumor activity through extrinsic and mitochondrial pathways.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2024 Oct; Vol. 151, pp. 107632. Date of Electronic Publication: 2024 Jul 11. - Publication Year :
- 2024
-
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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Structure-Activity Relationship
Molecular Structure
Cell Line, Tumor
Epoxy Compounds pharmacology
Epoxy Compounds chemistry
Epoxy Compounds chemical synthesis
Diterpenes, Kaurane pharmacology
Diterpenes, Kaurane chemistry
Diterpenes, Kaurane chemical synthesis
Antineoplastic Agents pharmacology
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Drug Screening Assays, Antitumor
Cell Proliferation drug effects
Apoptosis drug effects
Mitochondria drug effects
Mitochondria metabolism
Drug Design
Dose-Response Relationship, Drug
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 151
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 39003943
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107632