Antitumor Research on Artemisinin and Its Bioactive Derivatives

Cancer is the leading cause of human death which seriously threatens human life.The antimalarial drug artemisinin and its derivatives have been discovered with considerable anticancer properties.Simultaneously,a variety of target-selective artemisinin-related compounds with high efficiency have been discovered.Many researches indicated that artemisinin-related compounds have cytotoxic effects against a variety of cancer cells through pleiotropic effects,including inhibiting the proliferation of tumor cells,promoting apoptosis,inducing cell cycle arrest,disrupting cancer invasion and metastasis,preventing angiogenesis,mediating the tumor-related signaling pathways,and regulating tumor microenvironment.More importantly,artemisinins demonstrated minor side effects to normal cells and manifested the ability to overcome multidrug-resistance which is widely observed in cancer patients.Therefore,we concentrated on the new advances and development of artemisinin and its derivatives as potential antitumor agents in recent 5 years.It is our hope that this review could be helpful for further exploration of novel artemisinin-related antitumor agents.

An Artemisinin Derivative ART1 Induces Ferroptosis by Targeting the HSD17B4 Protein Essential for Lipid Metabolism and Directly Inducing Lipid Peroxidation

Artemisinin and its derivatives,commonly known as antimalarial drugs,have gradually come to be regarded as potential antitumor agents,although their cytotoxic efficacy and mechanisms of action remain to be settled.Herein,we report that an artemisinin analog,ART1,can potently induce ferroptosis in a subset of cancer cell lines.Structure–activity relationship(SAR)analysis reveals that both the endoperoxide moiety and the artemisinin skeleton are required for the antitumor activity of ART1.Aided with ART1-based small-molecule tools,chemical proteomic analysis identified the HSD17B4 protein as a direct target of ART1.HSD17B4 resides in peroxisomes and is an essential enzyme in the catabolism of very-long-chain fatty acids.Our results demonstrate that ART1 initiates ferroptosis through selective oxidation of the fatty acids in peroxisomes by hijacking the HSD17B4 protein without disturbing its enzymatic function,providing a promising mechanism to develop therapeutics for cancer treatment.

Antimalarial activity of a novel series of artemisinin-derived 1, 2, 3-triazole dimers

Objective: To obtain suitable artimisinin-based drug candidates with high antimalarial activity.Methods: Three different reaction schemes were used to synthesize a total of 15 artemisininbased compounds.The first synthetic scheme involved the synthesis of diazido aliphatic and aromatic compounds from commercially available dihalides and azido derivatives of artemisinin.The second scheme consisted of the reaction of dibromoaliphatic compounds with sodium azide in dimethylformamide which yielded the desired compounds.Artemisinin-based compounds on treatment with sodium azide and bromotrimethylsilane in dichloromethane produced the most potent compound GB-2.Another potent compound GB-1 was synthesized from artemisinin by treatment with alcohols in the presence of Aberlyst-15 in anhydrous dichloromethane.The third scheme involved the Huisgen 1,3-dipolar cycloaddition between the synthesized aliphatic and aromatic diazides and two alkyne derivatives of artemisinin to obtain the desired artemisinin dimers with average yields.Results: The best in vitro antiplasmodial activity was shown by the compound GB-2 registering IC_(50) value 0.066 μg/mL against chloroquine-sensitive and 0.865 μg/mL against chloroquineresistant strains of Plasmodium falciparum.It suppressed 59.0% parasitaemia in vivo of rodent malaria parasite Plasmodium berghei in Swiss albino model at 50 μg/kg body weight dosage.Molecular docking interactions of Plasmodium falciparum ATP6(PfATP6) protein revealed strong bonding of GB-2 with Thr255 residue which is likely to be the reason for excellent antimalarial activity of this compound.Conclusion: Two compounds GB-1 and GB-2 exhibited excellent in vitro antiplasmodial activity and fair in vivo antimalarial activity.Of the two, GB-2 showed better activity which could be attributed to its strong bonding interactions with Thr255 as evidenced from the molecular docking study.Study helped in identifying artemisinin analogues possessing good antimalarial properties and further research in structural alterations of the selected molecules should be carried out which may result in obtaining potent drug candidates against the malarial parasite.

Expanding the Therapeutic Spectrum of Artemisinin:Activity Against Infectious Diseases Beyond Malaria and Novel Pharmaceutical Developments

The interest of Western medicine in Traditional Chinese Medicine(TCM) as a source of drug leads/new drugs to treat diseases without available efficient therapies has been dramatically augmented in the last decades by the extensive work and the outstanding findings achieved within this kind of medicine. The practice of TCM over thousands of years has equipped scientists with substantial experience with hundreds of plants that led to the discovery of artemisinin(qinghaosu), which is extracted from the medicinal plant Artemisia annua L.(qinghao). The unexpected success of artemisinin in combating malaria has drawn strong attention from the scientific community towards TCM. Artemisinin was discovered by Youyou Tu in 1972. Since then, several novel pharmacological activities based on the well-known properties of the sesquiterpene lactone structure with the oxepane ring and an endoperoxide bridge have been unravelled. Beyond malaria, artemisinin and its derivatives(artemisinins) exert profound activities towards other protozoans(Leishmania, Trypanosoma, amoebas, Neospora caninum, and Eimeria tenella), trematodes(Schistosoma, liver flukes), and viruses(human cytomegalovirus, hepatitis B and C viruses). Less clear is the effect against bacteria and fungi. Based on the promising results of artemisinin and the first generation derivatives(artesunate, artemether, arteether), novel drug development strategies have been pursued.These included the synthesis of acetal-and non-acetal-type artemisinin dimeric molecules as well as developing nanotechnological approaches, e.g.artemisinin-based liposomes, niosomes, micelles, solid lipid nanocarriers, nanostructured lipid carriers, nanoparticles, fullerenes and nanotubes. The current review presents an overview on different aspects of artemisinins, including sources, chemistry, biological/pharmacological properties, types of infectious pathogens that are susceptible to artemisinins in vitro and in vivo, in addition to the advancement in their drug delivery systems utilizing pharmaceutical technology. It would be expected that different therapeutic strategies based on the second and third generation artemisinin derivatives and artemisinin-based drug technologies would be available in the near future to treat specific infectious diseases.

Alternatives to currently used antimalarial drugs: in search of a magic bullet

Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America.Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically.However,it is long before these novel drugs can hit the market,especially due to a scarcity of safety and efficacy data.To reduce the malaria burden,the Medicines for Malaria Venture(MMV)was established in 1999 to develop novel medicines through industry and academic partners’collaboration.However,no reviews were focused following various preclinical and clinical studies published since the MMV initiation(2000)to till date.We identify promising approaches in the global portfolio of antimalarial medicines,and highlight challenges and patient specific concerns of these novel molecules.We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies.Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further,especially for use in pregnant women.Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads.Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy.AQ-13 induced electrocardiac events,which led to prolonged QTc intervals.Tafenoquine,the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency,has raised significant concerns due to its hemolytic activity.Other compounds,including methylene blue(potential transmission blocker)and fosmidomycin(DXP reductoisomerase inhibitor),are available but cannot be used in children.At this stage,we are unable to identify a single magic bullet against malaria.Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission.Newer medicines have also raised concerns in terms of efficacy and safety.Overall,more evidence is needed to effectively reduce the current malaria burden.Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.