Antitumor activity of triterpenoid and its derivatives has attracted great attention recently. Our previous efforts led to the discovery of a series of NO‐donor betulin derivatives with potent antitumor activity. Herein, we prepared eight compounds derived from ursolic acid (UA). All the compounds were evaluated for their in vitro cytotoxicity against four human cancer cell lines (HepG‐2, MCF‐7, HT‐29 and A549). Among the compounds tested, compound 4a was found to be most active against HT‐29 (IC50=4.28 μm). Further biological assays demonstrated that compound 4a could induce cell cycle arrest at G1 phase and apoptosis in a dose‐dependent manner. In addition, compound 4a was found to upregulate pro‐apoptotic Bax, p53 and downregulate anti‐apoptotic Bcl‐2. All these results suggested that compound 4a is a potential candidate drug for the therapy of colon cancer.

Natural products have been widely considered as an important resource for new drugs or lead compounds. Sinomenine (SIN) and its derivatives exert antitumor activity via regulation of inflammatory mediators. For these reasons we synthesized three series of SIN derivatives (compounds 4 a-i, 7 a-c and 11 a-c) as antitumor agents from this natural product. All compounds were prepared by modification at the C1 and C4 positions of the A ring, the C4 position of the A ring, and the C6 and C7 positions of the C ring, respectively. All the derivatives were subjected to in vitro antitumor activity against HeLa, A549, HepG-2, MCF-7 and HT-29 cell lines. To observe the apoptotic induction of SIN derivatives and its mechanism, fluorescent staining and western blot assays were carried out for active compound against MCF-7. Based on the screening results, most of the SIN derivatives showed better antitumor activity than SIN. Some of them were found to possess broad-spectrum antitumor activity. Most notably, 11 c exhibited obvious antitumor activity in both cell lines with IC 50 values less than 11 μM. Besides, 11 c induced apoptosis of MCF-7 in a dose-dependent manner. Western blot assay demonstrated that 11 c inhibited IL-6-mediated activation of PI3K/Akt pathway. A docking study revealed that 11 c had stronger binding interaction with the residues of IL-6 than SIN. All these results indicate that 11 c may be a potential anti-breast cancer agent by directly targeting IL-6.

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),

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