Triterpenoid phthalimides as selective anti-cancer agents targeting mitochondrial apoptosis
Language English Country France Media print-electronic
Document type Journal Article
PubMed
39673861
DOI
10.1016/j.ejmech.2024.117126
PII: S0223-5234(24)01008-0
Knihovny.cz E-resources
- Keywords
- Apoptosis, Betulin, Betulinic acid, Cancer, Cell cycle regulation, Diels-Alder reaction, Mitochondria, Phthalates, Triterpenoids, Wittig reaction,
- MeSH
- Apoptosis * drug effects MeSH
- Phthalimides * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Mitochondria * drug effects metabolism MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation * drug effects MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Drug Screening Assays, Antitumor * MeSH
- Triterpenes * pharmacology chemistry chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Phthalimides * MeSH
- Antineoplastic Agents * MeSH
- Triterpenes * MeSH
Starting from benzyl 30-oxobetulinate and 30-oxobetulin diacetate, substituted dienes were synthesized and subjected to Diels-Alder reaction, yielding a variety of triterpenoid phthalates, phthalimides, and related derivatives. A total of 55 new compounds were prepared and tested for in vitro cytotoxic activity against eight cancer cell lines and two non-cancerous cell lines. Four compounds with IC50 values of 5 μM or lower were selected for further investigation. These compounds induced apoptosis in CCRF-CEM cells in a concentration-dependent manner, accompanied by mitochondrial depolarization and altered expression of key proteins involved in mitochondrial apoptosis. The compounds also disrupted DNA replication and transcriptional activity. Modulation of key proliferation pathways, including PI3K/Akt and STAT3, further supported the antiproliferative potential of these derivatives. Considering their high cytotoxicity and antiproliferative activity in CCRF-CEM cells, compounds 19, 26, 28, and 30 have been identified as promising candidates for further development.
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