The Synthesis And Antitumor Activity Of β-Elemene Derivatives

β-Elemene, extracted from the essential oils of a Chinese traditional medicinal herb Curcuma Wenyujin, is the main component of Elemene Emulsion developed in China as a novel antitumor drug. Experimental studies and clinic trials have demonstrated that it possesses potent antitumor activity both in vitro and in vivo, high specificity and lower liver and renal toxicities, as well as functions of immunity enhancement. These characteristics makeβ-elemene different from the conventional chemotherapeutic drugs and it should have heen given a fascinating and expectant usage. However, due to its poor water-solubility,β-elemene can only be used to patients as emulsion, whose instability, apparent vascular stimulation and a reqirement of high concentrations to reach a therapeutic effect limited its clinical use and antitumor activities.The development of pharmacy, effect mechanism and clinical use forβ-elemene were introduced briefly. Based on the studies ofβ-elemene derivatives, eighty-four compounds containing fatty amine, aromatic heterocycles, amino acid and carboxylic acid moieties were synthesized fromβ-elemene. Among them, seventy-eight compounds have been not reported in literatures. The structures of the target compounds were confirmed by MS, ¹H-NMR and IR spectra.To assess the anti-proliferation effect ofβ-elemene derivates, experiments with 'SRB assay' were performed in vitro. The results demonstrate that majority of these derivates inhibited the proliferation of human promyelocytic leukemia HL-60, human cervical HeLa and human gastric adenocarcinoma SGC-7901 cells and their 50% inhibitive concentrations (IC_50s) were lower thanβ-elemene. In order to evaluate the potential of being an anticancer drug, thirteenβ-elemene derivatives among them with better activity were tested by 'MTT assay' for their anti-tumor inhibitory activity in vitro against MCF-7 and MCF-7/Adr, all of them were not multidrug resistance for Adriamycin.To further investigate the antitumor effect, the cell growth inhibition, cytotoxicity and apoptosis induction of compounds DX-42, DX-54 and DX-56, the most potent agents among these derivatives, were measured in leukemia K562 cells. The results suggest that the inhibitory effect of these compounds on tumor cell growth is not due to apoptosis induction. It seems that these compounds inhibit cell growth through mTOR and/or AK.T activity inhibition. Following, The inhibitory effects of five compounds with better activity on H₂₂ and S₁₈₀ solid tumor in mice were studied in vivo. Among them four compounds were of both stronger inhibition and toxicity thanβ-elemene except compound DX-25.In vitro, the studies demonstrate that DX-25 inhibited the proliferation of HL-60, HeLa, SGC-7901, human hepatoma BEL-7402 and human hepatoma HepG₂ cells in a dose-and time-dependent manner, Optic microscope and fluorescence microscope photomicroseopical observation and DNA agarose gel electrophoresis showed that DX-25 could induce apoptosis in HeLa, SGC-7901 cells and that cell cycle was arrested at G₀/G₁ period. The further studies showed that the anti-proliferation mechanism of DX-25 is inducing tumor cells apoptosis by up-regulation of caspase-3 activity.Based on the results, the elementary structure-activity relationships of the compound mentioned above have been explored, which may make theoretical and practical bases for future work on the project searching for the antitumor drugs containingβ-elemene moiety.