Synthesis and antitumor potential of new arylidene ursolic acid derivatives via caspase‐8 activation

Abstract

Continuing our studies on NO-donating ursolic acid-benzylidene derivatives as potential antitumor agents, we designed and synthesized a series of new arylidene derivatives containing NO-donating ursolic acid and aromatic heterocyclic units.Compounds 5c and 6c showed a significant broad-spectrum antitumor activity.Compound 5c exhibited nearly three-to nine-fold higher cytotoxicity as compared with the parent drug in A549, MCF-7, HepG-2, HT-29, and HeLa cells, and it was also found to be the most potent apoptosis inducer of MCF-7 cells. More importantly, compound 5c arrested the MCF-7 cell cycle in the G1 phase, which was associated with caspase activation and a decrease of the Bcl-2/Bax ratio. Meanwhile, compound 5c caused changes in morphological features, dissipation of the mitochondrial membrane potential, and accumulation of reactive oxygen species. A docking study revealed that the nitroxyethyl moiety of compound 5c may form hydrogen bonds with caspase-8 amino acid residues (SER256 and HIS255). Together, these data suggest that NO-donating ursolic acid-arylidene derivatives are potent apoptosis inducers in tumor cells.antitumor activity, apoptosis inducer, NO donor prodrug, ursolic acid derivatives | INTRODUCTIONApoptosis (also called programmed cell death) was described to perform various functions in development. [1] It plays an important role not only in embryogenesis but also in the regulation of cell numbers and the elimination of unwanted cells. The previous literature pointed out that irregularity in apoptosis may cause a number of human diseases, such as neurodegenerative disorders, immunodeficiency, AIDS, and cancer. [2][3][4] Subsequent studies confirmed that apoptosis is one of the major pathways involved in the proliferation, migration, and invasion of tumor cells. Most of the cytotoxic compounds were reported to induce apoptosis in cancer cells. The developments of apoptosis inducers have become effective methods for cancer therapy. [5,6] In general, there is a balance between apoptosis and proliferation in normal cells. [7] The balance depends on the Bcl-2/Bax ratio. It is worth noting that high levels of Bcl-2/Bax ratio may increase the risk of cancer. An excess of Bcl-2 promotes migration and invasion of tumor cells. [8] Morphological alterations, including cell shrinkage, chromatin condensation, and nuclear fragmentation, are important features of tumor cell apoptosis. [9] It has been proved that most of the morphological changes are caused by caspase family proteases. Caspases are divided into three subfamilies, I (caspase-2, -8, -9, and -10),

Novel A-Ring Chalcone Derivatives of Oleanolic and Ursolic Amides with Anti-Proliferative Effect Mediated through ROS-Triggered Apoptosis

“…The strategy for modification of both the A-ring with chalcone introduction at C2 and derivatization of 28-COOH seems to be attractive because the obtained hybrid molecules while bearing two different pharmacophores can demonstrate high biological potential. For example, derivatives of the ursane type with p -chlorine-benzylidene- or 4-pyridynilidene- at C2 and nitrooxy ethyl substituents at C28 were found to be more cytotoxic than the parent drug (IC 50 ranged between 4.28–12.74 μm) and the lead derivatives could induce cell cycle arrest at the G1 phase and apoptosis in a dose-dependent manner via caspase-8 activation [ 27 , 30 ].…”

Cholesterol‐Based Conjugates: Synthesis, Characterization and In Vitro Biological Studies

“…[33] Ursolic acid and curcumin are also known to have anticancer activity against HeLa cells. [34][35] The IC 50 values of compounds 8 (63.834 μg/mL) and 9 (126.528 μg/mL) revealed promising cytotoxicity compared to the free cholesterol. Shao et al, [34] reported an IC 50 of 33.12 μg/ mL for ursolic acid on HeLa cells.…”

Sinomenine Derivatives: Synthesis, Antitumor Activity, and Apoptotic Induction in MCF‐7 Cells via IL‐6/PI3K/Akt/NF‐κB Signaling Pathway

“…Interestingly, our group has also demonstrated that NO-donating derivatives of natural product exhibit increased cytotoxicity on cancer cells. [33,34] These results encouraged us to design novel natural molecules derivatives bearing NO-donating moiety. In the present study, SIN was taken as leading compound and introduced nitroxy group to the 4-position of A ring.…”