STRUCTURAL MODIFICATION OF ALEPTEROLIC ACID FOR ANTI-CANCER DRUG DISCOVERY

摘要: Aleuritopteris argentea (SG Gmél.) Fée, also known as Cheilanthes argentea (SG Gmél.) Kunze, is a fern plant widely distributed in Asia [1]. This fern characteristically grows on limestone joints and wall joints with good drainage. It was alleged that the extract of the plant can promote blood circulation, regulate menstruation and prevent cancer, but scientific reports on its chemical constituents and exact mechanism are limited. Pioneer investigation on A. argentea by Hiroyuki Ageta et al isolated alepterolic acid as the major metabolite. In continuation of our research on medicinal ferns, recently we have obtained grams of alepterolic acid from A. argentea, which enabled the structural modification and subsequent activity evaluation. It is obviously noticed that 15-carboxy group and 3-hydroxyl group of alepterolic acid, like those two groups in ursolic acid and betulinic acid [2], are prone for easy structural modification, we thus initiated our preparation of derivatives by incorporation of amino moiety to 15-carboxyl group of alepterolic acid. More than 30 compounds were prepared and characterized by NMR, HRMS and HPLC. Biologically evaluation of anticancer potency showed that the newly semi-synthesized compounds exhibited better activity as compared to alepterolic acid itself. In the study of apoptotic mechanism of the best hit, it was found that compound induced apoptosis in Hela cancer cells via a mitochondria-dependent endogenous pathway. These findings encouraged the preparation of additional target compounds by click chemistry.