Synthesis Of New Artemisinin Derivatives And Preliminary Evaluation Of Their Antitumor Activities

Artemisinin and its derivatives have high anti-malarial activity and are one kind of the most effective drugs for the treatment of malarial. In recent years , many studies have shown that artemisinin and its derivatives also have antitumor, anti-parasitic diseases and immunosuppressive activities. As for antitumor activity, they have become a research focus, due to their wide antitumor spectrum with little side effects and their capability to reverse tumor multidrug resistance. Furthermore, they have no cross-resistance with the traditional anti-cancer drugs. The mechanism of their antitumor effects is that the concentration of Fe²⁺ in tumor cells is higher than that in normal ones, and Fe²⁺ can promote the break of the peroxide bridge in artemisinin to form free radicals , which can damage the biological macromolecules in the tumor cells.This work includes three parts:1. Dihydroartemisinin was obtained by the reduction of artemisinin with NaBH₄ (KBH4) as a reductant. Then, according to the specific tumor-targeting ability of polyunsaturated fatty acid, we chose docosahexaenoic acid as a tumor-targeting molecule and produced the ester of dihydroartemisinin and docosahexaenoic acid using DCC method. We prepared the ester of dihydroartemisinin and oleic acid using the same method for the purpose of comparision. Antitumor activities of those artemisinin derivatives against CA46, Molt4 and P388 cells were tested in vitro by MTT method. Results showed that DHA-DQHS had higher activity than artemisinin and dihydroartemisinin.2. Artesunate was synthesized by acylation of dihydroartemisinin with succinic anhydride as an acylating agent. According to the drug hybridization principles, we designed and synthesized several new artemisinin derivatives. Considering that solanesol and some NO donors had anti-cancer activities, we synthesized the conjugates by esterification of the carboxyl group of artesunate with the hydroxy group of solanesol and isosorbide mononitrate. Because some kinds of tumor cells produced more COX-2 than normal cells and non-steroidal anti-inflammatory drugs could inhibit the activity of COX, we produced the esters of dihydroartemisinin respectively with aspirin and ibuprofen using DCC and acyl chloride methods in order to obtain new conjugates with pleiotropic mechanisms against tumor. Antitumor activities of these conjugates against CA46, Molt4 and P388 cells were tested in vitro by MTT method. Except Ibuprofen-DQHS, the rest of these hybrids showed higher activities than artemisinin and dihydroartemisinin.3. We synthesized the amphipathic block copolymer MePEG-PLA, and then prepared the blank micelles, artemisinin-micelles and artemether-micelles by dialysis method. We studied the material ratio and dialysis conditions in order to produce two kinds of micelles with core-shell structure and rod-shaped structure. This work provided a clue for new pharmaceutical preparations of artemisinin and its derivatives.