Design, synthesis and biological evaluation of artesunate-Se derivatives as anticancer agents by inducing GPX4-mediated ferroptosis.

A series of organoselenium compounds based on the hybridization of artesunate (ART) scaffolds and Se functionalities (-SeCN and -SeCF3) were synthesized. The redox properties of artesunate-SeCN and artesunate-SeCF3 derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), and the results showed that compounds 2c, 2f and 3e have a good free radical scavenging activity. Their cytotoxicity was evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HCT116 (human colorectal adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), MCF-7 (human breast cancer cells). The MTT results showed that compared with ART and 5-FU, compound 2c exhibited potent in vitro antiproliferative activity in SW480, HCT116, and MCF-7 cancer cell lines, and was thus chose for further antitumor mechanism investigation. The antitumor mechanism study revealed that compound 2c induced ferroptosis in HCT116 cells by inhibiting the expression of GPX4 protein, accompanying by the up-regulation of intracellular ROS levels. Mitochondria in HCT116 cells exhibit depolarization of mitochondrial membrane potential (MMP) and ultrastructural changes in morphology, which indicated that 2c resulted in mitochondrial dysfunction and ferroptosis. Moreover, 2c could increase the levels of lipid peroxidation and ferrous ion, which further confirm that compound 2c may exert its antitumor effect through ferroptosis. Overall, these results suggest that the artesunate-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.

Artesunate-derived monomeric, dimeric and trimeric experimental drugs - Their unique mechanistic basis and pronounced antiherpesviral activity.

Human cytomegalovirus (HCMV) is a major human pathogen and is associated with severe pathology, such as life-threatening courses of infection in immunocompromised individuals and neonates. Currently, antiviral therapy is still hampered by a considerable toxicity of the available drugs and induction of viral resistance. Recently, we and others reported the very potent antiviral activity of the broad antiinfective drug artesunate in vitro and in vivo. Here, we investigated further optimized analogs including monomeric, dimeric and trimeric derivatives belonging to this highly interesting chemical group of experimental drugs (sesquiterpenes/trioxanes) and compared these to the previously identified trimeric artesunate compound TF27. We could demonstrate that (i) seven of the eight investigated monomeric, dimeric and trimeric artesunate derivatives, i.e. TF79, TF85, TF87, TF93.2.4, TF111, TF57a and TF57ab, exerted a strong anti-HCMV activity in primary human fibroblasts, (ii) the EC50 values ranged in the low to sub-micromolar concentrations and indicated a higher antiviral potency than the recently described artesunate analogs, (iii) one trimeric compound, TF79, showed a very promising EC50 of 0.03 ±â€¯0.00 µM, which even exceled the antiviral potency of TF27 (EC50 0.04 ±â€¯0.01 µM), (iv) levels of cytotoxicity (quantitative measurement of lactate dehydrogenase release) were low in a range between 100 and 30 µM and thus different from antiviral concentrations, (v) an analysis of protein expression levels indicated a potent block of viral protein expression, and (vi) data from a NF-κB reporter cell system strongly suggested that these compounds share the same antiviral mechanism. Taken together, our data on these novel compounds strongly encourages our earlier concept on the oligomerization and hybridization of artesunate analogs, providing an excellent platform for the generation of antiherpesviral drugs.