Studies On The Chemical Constituents And Bioactivities Of The Leaves Of Tripterygium Wilfordii

Tripterygium wilfordii Hook. F.(Celastraceae) is a traditional Chinese medicine distributed in the southern part of China, the roots of which have been used to treat cancer and inflammation. Recently, a traditional Chinese medicine preparation derived from a water/chloroform extract of the roots of T. wilfordii (the so-called "total multi-glycoside") has been employed in the clinical treatment of rheumatoid arthritis, skin disorders, male-fertility control, and other inflamatory and autoimmune diseases. Compared with the investigations of the roots of T. wilfordii, few chemical studies have been conducted on the leaves, although the leaves exhibited marked anti-inflammatory activity.Air-dried leaves of T. wilfordii (50kg) were extracted with80%ethanol. After evaporation of EtOH in vacuo, the aqueous residue was diluted with water and then partitioned with EtOAc. Seventy three compounds were isolated from the EtOAc extract by a variety of chromatographic techniques such as silica gel, sephadex LH-20, MPLC, and HPLC. Their structures were elucidated on the basis of UV, IR, HRESIMS,1D-and2D-NMR. Compounds1-20were new dihydroagarofuran sesquiterpene polyol esters, named Triptersinine A-T. Compounds30*-33*were new diterpenoids possessing a6/6/5tricyclic ring system, named Tripterlide A-D.34and35were new18(4â†'3) abeo-abietane diterpenoids.42*was new C13nor-isoprenoid.65was new phenylpropanoids. The other compounds were determined as known compounds on the basis of literatures.The anti-tumor activities of all the compounds were evaluated in vitro. Compounds35,36,38-40exhibited inhibitory activity on the HIF-1target. Among them,38showed most inhibitory activity with an IC50value of0.02μM.14,15, and65showed cytotoxicit yagainst HCT-8(human colon carcinoma) cell lines.38and39showed significant cytotoxicityagainst A549(human lung carcinoma), Bel-7402(human livercarcinoma), BGC-823(human stomach carcinoma), HCT-8(human colon carcinoma), and A2780(human ovarian carcinoma) cell lines. Compounds1,11,21,22, and27showed moderate inhibitory effects onnitric oxide production in LPS-induced macrophages at5μM.It is obviously that abietane diterpenoids were the bioactive substance of T. wilfordii. Based on triptolide (38), twenty four derivatives were prepared by the chemical reactions. The modification of14-OH of triptolide afforded derivatives A1-A16, and three by-products (A6-2, A6-3, A15-2). The anti-tumor effects evaluation exhibited that A8, A9, All, A12, A13, and A16inhibited the HIF-1target significantly; all derivatives inhibited the proliferation of five human cancer cell lines except A6-3, A14. As a result of the modification and bioassay of the derivatives of the14-OH of triptolide, we designed and prepared the derivatives A17-A24based on the modification of the C-5,14-OH of triptolide. A23showed significant inhibitory effect on the HIF-1target. A18exhibited moderate cytotoxicity against five human cancer cell lines.