artemisitene and artemisinin

Artemisinins are well-known antimalarial drugs with clinical safety. In addition to antimalarial effects, their anti-inflammatory and immunoregulatory properties have recently attracted much attention in the treatment of inflammatory diseases. However, these artemisinins only have sub-millimolar anti-inflammatory activity in vitro, which may pose a high risk of toxicity in vivo with high doses of artemisinins. Here, we identified another derivative, artemisitene, which can increase the activity of inhibiting the NLRP3 pathway by more than 200-fold through introducing a covalent binding group while retaining the peroxide bridge structure. Mechanistically, artemisitene inhibits the production of ROS (especially mtROS) and prevents the assembly and activation of NLRP3 inflammasome, thereby inhibiting IL-1β production. In addition, it can also block IL-1β secretion mediated by NLRC4 and AIM2 inflammasome and IL-6 production. Furthermore, treatment with artemisitene significantly attenuated inflammatory response in DSS-induced ulcerative colitis. Our work provides a potential artemisinin derivative, which is worthy of further structural optimization based on pharmacokinetic properties as a drug candidate for inflammatory disorders.

Topics: Antimalarials; Artemisinins; Colitis, Ulcerative; Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species

Cancer chemotherapeutic agents such as doxorubicin are DNA damage inducers that also kill normal cells, making them highly toxic to cancer patients. To improve the efficacy and safety of chemotherapy, it is important to develop new chemotherapeutic agents that selectively kill cancer cells. Here we demonstrate that artemisitene (ATT), a natural derivative of the antimalarial drug artemisinin, selectively induces DNA double-stranded breaks (DSBs) and apoptosis in various human cancer cells by suppressing the expression of topoisomerases in human cancer cells. ATT effectively kills human cancer cells without apparent cytotoxicity on normal human cells or mouse liver and kidney. We discovered that c-Myc induces the expression of topoisomerases to prevent accumulation of DNA damage in human cancer cells. ATT selectively destabilizes c-Myc in human cancer cells by promoting the ubiquitination of c-Myc through the specific induction of the c-Myc E3 ligase NEDD4. Therefore, ATT represents a promising new chemotherapeutic drug candidate that can eliminate human cancer cells with minimized cytotoxic effects on normal cells.

Topics: Animals; Antimalarials; Antineoplastic Agents; Apoptosis; Artemisinins; Carcinogenesis; Cell Line, Tumor; DNA; DNA Damage; DNA Topoisomerases, Type II; Humans; Mice; Mice, Nude; Nedd4 Ubiquitin Protein Ligases; Proto-Oncogene Proteins c-myc; Topoisomerase II Inhibitors; Ubiquitination

Artemisia annua hot water infusion (tea) has been used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. High performance liquid chromatography (HPLC) and mass spectrometric analyses were employed to determine the metabolite profile of tea including the concentrations of artemisinin (47.5±0.8 mg L(-1)), dihydroartemisinic acid (70.0±0.3 mg L(-1)), arteannuin B (1.3±0.0 mg L(-1)), isovitexin (105.0±7.2 mg L(-1)) and a range of polyphenolic acids. The tea extract, purified compounds from the extract, and the combination of artemisinin with the purified compounds were tested against chloroquine sensitive and chloroquine resistant strains of P. falciparum using the DNA-intercalative SYBR Green I assay. The results of these in vitro tests and of isobologram analyses of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene) extracted from A. annua with significant (IC50 <1 μM) anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain at a combination ratio of 1:3 (artemisinin to purified compound). In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B's potentiation of artemisinin.

Topics: Antimalarials; Artemisia annua; Artemisinins; Cinnamates; Depsides; Drug Synergism; Plant Extracts; Plasmodium falciparum; Rosmarinic Acid

Nucleophilic additions of lithium keto and ester enolates and mono- and bifunctional Grignard reagents to artemisitene provided C-16-derived artemisinin monomers, dimers, trimers, and tetramers whose antimalarial and cytotoxic activities have been evaluated.

Topics: Animals; Antimalarials; Antineoplastic Agents; Artemisinins; Cell Line; Chlorocebus aethiops; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Molecular Conformation; Plasmodium falciparum; Polymers; Sesquiterpenes; Structure-Activity Relationship; Tumor Cells, Cultured

The antimalarial activity of a number of artemisinin derivatives, both newly synthesized and currently used as drugs, against Plasmodium falciparum in culture shows a correlation with their affinity of binding with ferroprotoporphyrin IX, as measured from the spectral change of the latter. The new C-16-functionalized artemisinin derivatives were obtained through a novel one-pot synthesis of artemisitene (2) from naturally abundant artemisinin (1), followed by Michael addition with nucleophiles. The correlation points to the biological significance of the interaction of these derivatives with ferroprotoporphyrin IX and may provide a basis for primary screening of peroxidic antimalarials of similar structures.

Topics: Animals; Antimalarials; Artemisinins; Cells, Cultured; Heme; Magnetic Resonance Spectroscopy; Molecular Structure; Plasmodium falciparum; Sesquiterpenes