1. Novel triterpenoid pyrones, phthalimides and phthalates are selectively cytotoxic in CCRF-CEM cancer cells – Synthesis, potency, and mitochondrial mechanism of action.
- Author
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Kazakova, Anna, Frydrych, Ivo, Jakubcová, Nikola, Pokorný, Jan, Lišková, Barbora, Gurská, Soňa, Džubák, Petr, Hajdúch, Marián, and Urban, Milan
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PHTHALIMIDES , *CANCER cells , *PHTHALATE esters , *CELL cycle , *MITOCHONDRIA , *TRITERPENOIDS , *TRIPHENYLAMINE , *DNA synthesis - Abstract
A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC 50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f , and dihydrophthalimide 2h have been selected for further development. [Display omitted] • A set of novel triterpenoid pyrones, phthalimides and phthalates was synthesized. • Six compounds with high in vitro cytotoxicity in CCRF-CEM cells was identified. • All compounds induce apoptosis via the mitochondrial intrinsic pathway. • Pyrones 1f , 2f , and dihydrophthalimide 2h were selected for further development. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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