Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties.
ABSTRACT Artemisinins are plant products with a wide range of medicinal applications. Most prominently, artesunate is a well tolerated and effective drug for treating malaria, but is also active against several protozoal and schistosomal infections, and additionally exhibits anti-angiogenic, anti-tumorigenic and anti-viral properties. The array of activities of the artemisinins, and the recent emergence of malaria resistance to artesunate, prompted us to synthesize and evaluate several novel artemisinin-like derivatives. Sixteen distinct derivatives were therefore synthesized and the in vitro cytotoxic effects of each were tested with different cell lines. The in vivo anti-angiogenic properties were evaluated using a zebrafish embryo model. We herein report the identification of several novel artemisinin-like compounds that are easily synthesized, stable at room temperature, may overcome drug-resistance pathways and are more active in vitro and in vivo than the commonly used artesunate. These promising findings raise the hopes of identifying safer and more effective strategies to treat a range of infections and cancer.
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ABSTRACT: Introduction: The isolation of artemisinin from an ancient Chinese remedy in the early 1970s heralded the beginning of a new era in antimalarial drug therapy culminating in artemisinin-based combination therapies currently being the mainstay of malaria treatment worldwide. Ongoing research on this compound and its derivatives has revealed its potential use in treating other infectious and noninfectious diseases. Areas covered: This review provides a summary of patents published globally from January 2006 to June 2012 covering promising artemisinin derivatives and artemisinin-based drug combinations developed for use in various therapeutic areas. Expert opinion: The diversity of semi-synthetic artemisinin derivatives has been limited to the same design strategy of modifying the artemisinin molecule at the same positions due to inherent synthetic challenges. To address this, future endeavors should include: the use of biotransformation strategies to modify other positions in the sesquiterpene ring while retaining the endoperoxide bridge; the design and synthesis of synthetic ozonides based on the pharmacophoric endoperoxide motif and drug repositioning approaches to artemisinin-based combination therapy. A better understanding of the mechanism of action of artemisinin derivatives and their biomolecular targets may provide an invaluable tool for the development of derivatives with a wider array of activity and greater clinical utility than currently appreciated.Expert Opinion on Therapeutic Patents 09/2012; 22(10):1179-203. · 3.53 Impact Factor
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ABSTRACT: We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.PLoS ONE 01/2013; 8(12):e82962. · 3.73 Impact Factor