Design, synthesis and in vivo anticancer activity of novel parthenolide and micheliolide derivatives as NF-κB and STAT3 inhibitors
| Autor: | Kailu Zheng, Bing-Lin Zeng, Shen Longying, Jinping Hu, Yu Cheng, Yan Li, Liu Shuoxiao, Pan Xiandao |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
STAT3 Transcription Factor Antineoplastic Agents Mice Inbred Strains Pharmacology 01 natural sciences Biochemistry chemistry.chemical_compound Mice Sesquiterpenes Guaiane Structure-Activity Relationship Immune system In vivo Drug Discovery medicine Tumor Cells Cultured Animals Humans Parthenolide STAT3 Cytotoxicity Molecular Biology Cell Proliferation Temozolomide biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry NF-kappa B NF-κB Neoplasms Experimental 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Apoptosis Drug Design biology.protein Drug Screening Assays Antitumor Sesquiterpenes medicine.drug |
| Zdroj: | Bioorganic chemistry. 111 |
| ISSN: | 1090-2120 |
| Popis: | Parthenolide and micheliolide have attracted great attention in anticancer research due to their unique activities. In this study, thirteen parthenolide derivatives and twenty-three micheliolide derivatives were synthesized. Most synthesized compounds showed higher cytotoxicity than parthenolide or micheliolide. The in vivo anticancer activity of several representative compounds was evaluated in mice. One micheliolide derivative, 9-oxomicheliolide (43), showed promising in vivo antitumor activity compared with clinical drugs cyclophosphamide or temozolomide. Compound 43 was particularly effective against glioblastoma, with its tumor inhibition rate in mice comparable to the drug temozolomide. The discovery of compound 43 also demonstrates the feasibility of developing anticancer micheliolide derivatives by modification at C-9 position. Anticancer mechanism studies revealed that 9-oxomicheliolide exhibited inhibition effect against NF-κB and STAT3 signaling pathways, as well as induction effects of cell apoptosis. It is postulated that 9-oxomicheliolide is likely to be a modulator of the immune system, which regulates the anticancer immune responses. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect