The stereoselective synthesis of privileged epimer of C-10 carba artemisinins and the effect of substituted groups with different acid-base properties on the antimalarial activity / 药学学报

ABSTRACT

Artemisinin is a sesquiterpene lactone natural product that contains an endoperoxide bond. Artemisinin has various biological activities including antimalarial, anti-tumor, antiviral and anti-fibrotic activity. Owing to the poor pharmacokinetic properties of artemisinin, its derivatives are currently used in clinic and frequently reported in literature. Although numerous derivatives of artemisinin have been reported, no study has been carried out yet to study the effect of substituted groups with different acid-base property on the antimalarial activity. Among these derivatives, the C-10 carbon artemisinin derivatives are often reported, and their corresponding 10β epimer show much better antimalarial activity than 10α epimer with large-sized substitute. However, there is currently no stereoselective synthesis to efficiently prepare the privileged 10β epimer of C-10 carba artemisinin. To address these two scientific questions, we herein first report an optimized method to stereoselectively synthesize the 10β epimer of C-10 carba artemisinin (98∶2 d.r.). Second, we employed the optimized method to synthesize a series of C-10 carba artemisinin derivatives with different acid-base properties. The antimalarial examination indicated that those derivatives with neutral groups or basic group of short chain showed similar antimalarial activity as dihydroartemisinin (DHA). The acidic group could dramatically decrease the antimalarial effect and was more than 22-fold less effective than DHA or the neutral ones. This study will shed light on the development of new generation of artemisinin derivatives with potent activity.