青蒿素10位碳取代优势构型的立体选择性合成及不同酸碱性基团对其抗疟活性的影响

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

青蒿素是一种含过氧桥键结构的倍半萜内酯类天然产物,具有抗疟、抗肿瘤、抗病毒和抗纤维化等药理活性。由于青蒿素原药的药代性质较差,目前在临床使用及在科研中报道的都是青蒿素的衍生物。尽管有很多青蒿素衍生物的报道,但是不同酸碱性基团对青蒿素抗疟活性的影响并没有报道。此外,青蒿素10位以C-C键相连的衍生物经常报道,并且10位C-C键衍生物10β异构体的抗疟活性是其10α异构体的20倍。但是,目前并没有高效的不对称合成方法用于合成10位C-C键衍生物的优势构型(10β异构体)。针对这两个科学问题,首先优化反应条件确立了青蒿素10位碳取代衍生物的优势构型的不对称合成方法,显著提高了10β异构体的比例(98∶2 d.r.)。其次,利用优化的合成方法,在青蒿素10位通过C-C键引入了酸性、碱性和中性基团。抗疟活性测试表明,含有中性取代基的化合物DHA-O1、DHA-O2和含有碱性取代基的短链化合物DHA-N2具有与双氢青蒿素(DHA)相当的抗疟活性, IC_(50)值分别为11.39±4.66、14.04±3.14和9.17±4.57 nmol·L^(-1)。酸性取代基显著降低青蒿素的抗疟活性,其对应化合物DHA-A1和DHA-A2的活性相比双氢青蒿素降低了22倍多。本研究为获得抗疟活性更高的青蒿素衍生物和类似物提供了理论依据和技术基础。

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 10βepimer show much better antimalarial activity than 10a epimer with large-sized substitute.However,there is currently no stereoselective synthesis to efficiently prepare the privileged 10βepimer of C-10 carba artemisinin.To address these two scientific questions,we herein first report an optimized method to stereoselectively synthesize the 10βepimer 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.