tripdiolide and triptolide

Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antimalarials; Artemisinins; Catechin; Diterpenes; Drug Discovery; Drugs, Chinese Herbal; Epoxy Compounds; Functional Food; Humans; Medicine, Chinese Traditional; Phenanthrenes

A divergent route was developed for the formal total synthesis of triptolide, triptonide, and tripdiolide, as well as a total synthesis of 16-hydroxytriptolide and their analogues in an enantioselective form. Common advanced intermediate 5 was concisely assembled by employing an indium(III)-catalyzed cationic polycyclization reaction and a palladium-catalyzed carbonylation-lactone formation reaction as key steps. This advanced intermediate was readily converted to the above natural products by using palladium-catalyzed cross-coupling or the Claisen rearrangement reaction as key steps. Additionally, preliminary structure-cytotoxic activity relationship studies of C13 suggested that it might be a new modification site that could still retain the cytotoxicity.

Topics: Catalysis; Diterpenes; Epoxy Compounds; Indium; Lactones; Palladium; Phenanthrenes; Triterpenes

To date, Kaposi sarcoma has not been mentioned among the adverse effects of triptolide/tripdiolide, ethyl acetate extracts or polyglycosides of the Chinese herbal remedy Tripterygium wilfordii Hook F.. A patient was diagnosed with rheumatoid arthritis at the age of 29 years. She underwent treatment with corticosteroids, methotrexate and gold sodium thiosulfate, and was chronically taking ketoprofen. At the age of 59 years she started to take a powder (≈2 g/day) from a Chinese physician for treatment of rheumatoid arthritis. This powder was supplied to her regularly for 10 years. At the age of 69 years, multiple soft, violaceous to dark-red patches, plaques, nodules and blisters of varying sizes appeared on a background of severely edematous skin on her legs, and later on her arms. Biopsy specimens of the leg lesions were diagnostic for human herpesvirus 8-associated Kaposi sarcoma. Triptolide (235 µg/1 g) and tripdiolide were found in the Chinese powder by the use of Liquid Chromatography Electrospray Ionization Mass Spectrometry. Administration of the powder was stopped and medication with paclitaxel was introduced. General condition of the patient improved and skin lesions diminished significantly.. This case indicates a possible association between triptolide/tripdiolide chronic intake and development of human herpesvirus 8-associated Kaposi sarcoma. Triptolide/tripdiolide could contribute to development of Kaposi sarcoma by reactivation of latent human herpesvirus 8, permitted by immunosuppression induced by triptolide.

Topics: Adult; Aged; Arthritis, Rheumatoid; Diterpenes; Edema; Epoxy Compounds; Female; Humans; Immunosuppressive Agents; Leg; Middle Aged; Phenanthrenes; Powders; Sarcoma, Kaposi; Skin Neoplasms

An accurate and selective method for the simultaneous determination of triptolide, tripdiolide and tripterine in human urine using hydrocortisone as an internal standard (IS) by high-performance liquid chromatography coupled with atmospheric-pressure chemical ionization mass spectrometry in negative ion mode has been developed. After triptolide, tripdiolide and tripterine in human urine were extracted with ethyl acetate and cleaned by solid-phase extraction with C(18) cartridges, a satisfactory separation was achieved on an XDB C(18) short column (30 x 2.1 mm i.d., 3 microm) using the mobile phase of acetic acid-ammonium acetate (5 mmol/L, pH = 4.5)-acetonitrile-methanol in gradient elution. Detection was operated by APCI in selected ion monitoring mode. The target ions m/z 359, m/z 375, m/z 449 and m/z 419 were selected for the quantification of triptolide, tripdiolide, tripterine and IS, respectively. The linear range was 1.0-100.0 ng mL(-1), and the limits of quantification in human urine were found to be 0.1-0.5 ng mL(-1) for the three compounds. The precisions (CV%) and accuracies were 6.6-12.9 and 85.1-97.0%, respectively. The developed method could be applied to the determination of triptolide, tripdiolide and tripterine in human urine for diagnosis of the intoxication and for forensic purposes.

Topics: Chromatography, High Pressure Liquid; Diterpenes; Epoxy Compounds; Humans; Hydrocortisone; Linear Models; Models, Chemical; Pentacyclic Triterpenes; Phenanthrenes; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Triterpenes

Triptolide and tripdiolide are thought to be active components of the Chinese antirheumatic herbal remedy Tripterygium wilfordii Hook F, which has been shown to be effective in treating murine lupus nephritis. This study was undertaken to examine the therapeutic effect of triptolide and tripdiolide on established lupus nephritis in (NZB x NZW)F1 mice.. (NZB x NZW)F1 mice were treated with vehicle, triptolide, or tripdiolide for 15 weeks beginning at the age of 29 weeks (after the development of lupus nephritis). Body weight, proteinuria, and anti-double-stranded DNA (anti-dsDNA) antibodies were monitored, and the kidney and spleen were assessed histologically. Culture supernatants of spleen mononuclear cells were assayed for cytokines.. By 28 weeks, most (NZB x NZW)F1 mice had developed lupus nephritis. Vehicle-treated mice exhibited progressive proteinuria, hypoalbuminemia, elevated blood urea nitrogen (BUN) levels, and evidence of severe nephritis. In contrast, proteinuria and BUN levels were significantly reduced in mice treated with either triptolide or tripdiolide as compared with those treated with vehicle. There was no hypoalbuminemia or apparent evidence of lupus nephritis in mice treated with either of the 2 diterpenoids. At 44 weeks of age, the survival rate in mice treated with vehicle (35.7%) was markedly lower than that in mice treated with either triptolide (87.5%) or tripdiolide (88.2%). The mean level of anti-dsDNA antibody in mice treated with tripdiolide was lower than that in the vehicle-treated mice upon completion of the treatment course. Production of tumor necrosis factor, interleukin-6, and monocyte chemoattractant protein 1 by spleen cells was also decreased after diterpenoid therapy.. Therapy with triptolide or tripdiolide significantly ameliorated lupus nephritis in (NZB x NZW)F1 mice, reduced cytokine and chemokine production, and prolonged survival.

Topics: Animals; Disease Models, Animal; Diterpenes; Drugs, Chinese Herbal; Epoxy Compounds; Female; Immunosuppressive Agents; Lupus Nephritis; Mice; Phenanthrenes; Spleen; Tripterygium

The extract of Tripterygium wilfordii Hook F. (TwHF), which showed anti-inflammatory and immunosuppressive activities in human clinical trials for rheumatoid arthritis, was subjected to the activity-guided fractionation and spectroscopic characterization of bioactives. A tetrahydrofuran lignan, tripterygiol (1), and eight known compounds, all capable of suppressing pro-inflammatory gene expression were identified. Most of the pharmacological activity of the extract can be attributed to triptolide, its most abundant and active component, with some contribution from tripdiolide.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Chemical Fractionation; Diterpenes; Epoxy Compounds; Immunosuppressive Agents; Mice; Nuclear Magnetic Resonance, Biomolecular; Phenanthrenes; Plant Extracts; Tripterygium

Crude extracts derived from the root of Tripterygium wilfordii Hook f (TWHf) have previously been demonstrated to have immunosuppressive properties and have been used as anti-rheumatic therapy in Chinese traditional medicine. Although these extracts contain a large number of chemical components, the precise nature of the compound(s) responsible for this therapeutic effect has not been established with certainty. An aqueous extract of TWHf was resolved into chemical components by medium-pressure and high-performance liquid chromatography. Immunosuppressive fractions were identified with a mixed lymphocyte reaction (MLR) and chemically characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. Two major peaks of immunosuppressive activity were identified. These were the closely related diterpenoid triepoxides, triptolide and tripdiolide. No other immunosuppressive compounds were identified using MLR as the biologic screening assay. Triptolide and tripdiolide may be responsible for the anti-rheumatic properties of crude aqueous extracts of TWHf and represent a novel class of immunosuppressive drugs with potential clinical utility.

Topics: Animals; Cells, Cultured; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Diterpenes; Drugs, Chinese Herbal; Epoxy Compounds; Immunosuppressive Agents; Lymphocyte Culture Test, Mixed; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenanthrenes; Spleen

Extracts of the Chinese medicinal plant, Tripterygium wilfordii, cause reversible infertility in male animals. Sub-fractionation studies have now revealed that the plant extracts contain a number of compounds which are potent antifertility agents in male mammals, including the diterpenes triptolide and tripdiolide and an isomer of the latter. A triptolide, 12,13-chlorohydrin, which is a transformation product formed reversibly by interaction of triptolide with HCl, was also found to be active.

Topics: Animals; Biological Assay; Chromatography, High Pressure Liquid; Diterpenes; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Epoxy Compounds; Fertility; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Organ Size; Phenanthrenes; Rats; Serial Extraction; Sperm Count; Sperm Motility; Spermatocidal Agents; Tablets; Testis; Weight Gain

Topics: Alkylating Agents; Antineoplastic Agents; Diterpenes; Drugs, Chinese Herbal; Epoxy Compounds; Phenanthrenes

Topics: Antineoplastic Agents; Diterpenes; Epoxy Compounds; Ethers, Cyclic; Lactones; Models, Chemical; Phenanthrenes; Plants, Medicinal