Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties.
Bottom Line: 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.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.
Affiliation: Dafra Pharma Research & Development, Slachthuisstraat, Turnhout, Belgium.Show MeSH
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Mentions: To identify novel artemisinin-like compounds for evaluation of efficacy in different models, we synthesized several acetal and non-acetal derivatives of DHA. Esters (Fig. 2) were made by reacting DHA with corresponding anhydrides or acid chloride in basic medium in the presence of triethylamine, as reported . The ether and amine (Fig. 3) were made by reacting DHA with a Levis acid forming an oxonium ion , that reacts with nucleophiles, such as alcohol or amine, and converts to ether (or amine) derivatives. In the absence of nucleophiles, it forms an anhydro product 4, or it can be further reduced in the presence of Et3SiH to obtain the product 3. Compound 4 was further converted to alcohol 5a-b (5a major product) by addition of borane followed by hydrogen peroxide and aqueous NaOH (Fig. 4). A similar reaction was previously reported .
Affiliation: Dafra Pharma Research & Development, Slachthuisstraat, Turnhout, Belgium.