38748-32-2

Basic information

• Product Name: Triptolide
• Synonyms: PG490;TRIPTOLIDE;TRIPTOLIDE, TRIPTERYGIUM WILFORDII;,7as,7bs,8as,8bs)-;8b,9,10-decahydro-6-hydroxy-8b-methyl-6a-(1-methylethyl)-,(3bs,4as,5as,6r,6ar;triptolid;TRIPTOLIDE TLC;TRIPTOLIDE95%
• CAS NO: 38748-32-2
• Molecular Formula: C₂₀H₂₄O₆
• Molecular Weight: 360.4
• EINECS: 300-006-3
• Product Categories: Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Natural Anti-cancer Medical Materials and It's Derivatives;Nutritional Ingredients;Chiral Reagents;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;Inhibitors
• Mol File: 38748-32-2.mol

Chemical Properties

• Melting Point: 226-227°C
• Boiling Point: 412.43°C (rough estimate)
• Flash Point: 220.7 °C
• Appearance: white to off-white/solid
• Density: 1.1656 (rough estimate)
• Vapor Pressure: 5.51E-17mmHg at 25°C
• Refractive Index: 1.4450 (estimate)
• Storage Temp.: 2-8°C
• Solubility: DMSO: soluble
• PKA: 14.25±0.60(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• Merck: 14,9747
• CAS DataBase Reference: Triptolide(CAS DataBase Reference)
• NIST Chemistry Reference: Triptolide(38748-32-2)
• EPA Substance Registry System: Triptolide(38748-32-2)

Safety Data

• Safety Statements: 22-24/25
• RIDADR: 2811
• WGK Germany: 3
• RTECS: YK7751000
• HazardClass: 6.1
• PackingGroup: I
• Hazardous Substances Data: 38748-32-2(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Triptolide is used as an immunosuppressant and anti-inflammatory agent for its potent activity in inhibiting eukaryotic transcription and blocking transactivation of NFkB. It is also used as an antiproliferative agent in cancer treatment, showing synergistic effects with other anticancer agents.
Used in Anti-Inflammatory Applications:
Triptolide is used as an anti-inflammatory agent for its ability to inhibit the inflammatory response and decrease the production of TNF-a, IL-1b, and IL-6 in a rat model of rheumatoid arthritis.
Used in Cancer Treatment:
Triptolide is used as an anticancer agent in the treatment of various types of cancer due to its potent antiproliferative activity in 60 cancer cell lines and its synergistic effects when combined with other anticancer agents.

Tripterygium wilfordii

There are four species under the genus Tripterygium in the world, and all are native to China, with three species being medicine. Tripterygium wilfordii is a woody climber, 2-3 meters high. Branchlets are reddish and with brown angular, with oblong tuberculate projections and iron brown hairs. Flowering period is from May to June. Fruit ripening period is from August to September. It grows in shady and humid slopes, valleys, bushes besides streams and secondary miscellaneous forests, with the distribution in the south of the Yangtze River, Anhui, Zhejiang, Fujian, Taiwan, Jiangxi, Hunan, Guangdong and even the southwest provinces. It is harvested in summer or autumn. It is bitter and poisonous, and can be used as insecticide, anti-inflammatory and detoxification. This product is poisonous, thus be careful when orally taking in. 1.Treatment of rheumatoid arthritis: smash the roots and leaves of Tripterygium wilfordii and apply it externally. Remove it half an hour later, otherwise blister could occur. (Jiangxi, " Handbook of Herbs"). 2. Treatment of skin itchiness: smash the leaves of Tripterygium wilfordii and apply it ( "Medicinal Flora in Hunan"). 3. Treatment of snake strand sore: grind the flowers of Tripterygium wilfordii and the root of three-nerved spicebush, and apply it the affected area (“ Medicinal Flora in Hunan ").

Anti-inflammatory and immunosuppressive effects

Triptolide is an epoxy diterpene lactone compound that extracted from the roots, leaves, flowers and fruits of Tripterygium wilfordii (Celastraceae). Triptolide, with alkaloids like wilfordine, wilforine, wilforgine, Wilfortrine, wilfozine and Wilfornine, constitutes the main active ingredient of Tripterygium extraction. It is insoluble in water, soluble in methanol, dimethyl sulfoxide, ethanol, ethyl acetate, chloroform ect. It has anti-inflammatory and immunosuppressive effects: with the application of 10μg/kg sc Triptolide in continuous 10 days, the croton oil-induced ear edema in mice can be reduced. The in vitro tests with the application of 0.05~1μg/ml Triptolide in continuous 7 days showed this product has a stabilizing effect on sheep erythrocyte membrane; with the application of 75,150mg/kgsc Triptolide in continuous 7 days, the total complement levels of rat serum significantly increased, and the formation of hemolysin antibody in primary immune response was significantly inhibited, but no significant inhibition was found in the formation of hemolysin antibody in the second immune response; with the application of 150μg/kg ig Triptolide in continuous 7 days, a certain degree of inhibition in mouse peritoneal phagocytic function; with the application of 300μg/kg sc Triptolide in continuous 15 days, the croton oil-induced ear edema in mice was inhibited; with the application of 75,150μg/kgsc Triptolide in continuous 14 days, the carrageenan paw swelling in rat was inhibited; with the application of 0.22~4.44μg/ml Triptolide in Polygalatenuifolia extraction, a protective effect on RBCM of rats was showed; with the application of 0.25,1mg/kg ip Triptolide, antibody production and secretion in mice were inhibited (QHS method); with the application of 50,500ng/ml concentration, proliferative responses of T cell and B cell were significantly inhibited; with the application of 5,50,500ng/ml Triptolide in vitro and 0.5,0.75,1mg/kg ip drug in vivo, the production of mouse spleen cells IL-2 was significantly inhibited; with the application of 0.1~1μg/ml Triptolide in vitro, Con A-induced lymphocyte growth was inhibited; with the application of 0.5~10μg/L Triptolide the mixed lymphocyte culture (MLC) was inhibited: after 60Co irradiation, the mixed lymphocyte that induced with the concentration of 5,10μg/L Triptolide inhibited the second MLC, showing that triptolide can induce suppression T cells (Ts); with the application of 0.12~0.5mg/kg ip Triptolide, the DNFB-induced DTH in mice was significantly inhibited; with the application of 0.25,0.5mg/kg Triptolide, the secretion activity of mice spleen cells IL-2 was inhibited, and the increased DTH responses that induced by high-dose cyclophosphamide was also inhibited; with the application of 0.25mg/kg Triptolide, mouse thymus Th/Ts cell ratio reduced. Experimental results indicate that triptolide has immunosuppression, and the mechanism may be related to inhibition of Th cells and secretion activity of IL-2 and inducing Ts cells. The above information is edited by the lookchem of Cheng Jingmin.

Anti-cancer effects

In recent years, a large number of in vitro and in vivo studies demonstrated this product has good anti-tumor activity to a variety of cancers such as leukemia, breast cancer, pancreatic cancer and lung cancer. Recent studies have found that triptolide not only affects certain proteins and signaling pathways specifically, but also inhibits broad gene transcription, but the mechanism remains to be further clarified. Yu Qiang group in Shanghai Institute of Materia Medica of Chinese Academy of Sciences studied in-depth the molecular mechanisms of Triptolide in suppressing broad gene transcription. The study found that Triptolide inhibited gene transcription by promoting the phosphorylation of the largest and most important functional subunit Rpb1 in RNA polymerase II, and subsequent Rpb1 ubiquitin degradation. PTEF-b, the upstream kinases of Rpb1, plays a positive role in the regulation of phosphorylation process of Rpb1 that induced by Triptolide. The study also found that Triptolide could induce DNA damage. These results indicate that triptolide suppresses broad gene transcription by causing DNA damage in cells and thus activating the P-TEFb, which can phosphorylate Rpb1 and cause Rpb1 degradation.

Using TLCS method to determine the content of triptolide

1. Chromatographic conditions: silica gel G-CMCNa plate; chloroform-ether (2: 1) as developing solvent; 2% 3,5-dinitro-benzoic acid ethanol solution and 2mol/L Sodium hydroxide ethanol solution. Mix them with the ratio 1: 3 before use as the chromogenic agent, spray the mixture and view the results under natural light. 2. The preparation of the reference solution: Weigh appropriate triptolide accurately as the reference substance, and add chloroform to make the reference solution with 1.528mg triptolide per ml. 3. Preparation of sample solution: Weigh appropriate dried herbs accurately, and make reflux extraction three times by adding ethanol, with 3 hours each time. Combine the extraction and recover ethanol to dryness, and then extract triptolide by dissolving in ethyl acetate until no triptolide presence in TLC, and recover ethyl acetate to get the extract. weigh accurately 0.4g extract powder, which has been dried at 90 ℃to constant weight and dissolve it in 5ml of dichloromethane, and mix with 8g neutral alumina, and evaporate the dichloromethane and transferre to a Soxhlet extractor, and reflux for 3h with petroleum ether (60~90 ℃), and discard the petroleum ether and remove the filter cartridge, shake off the solvent, and then reflux for 5h by placing it in an extractor with 70ml chloroform, recover chloroform to dryness and cool it, and dissolve it to precise 3ml chloroform as the sample solution. 4. Determination: precisely drawing 10μl sample solution and 2,7μl reference solution, and point them to the same piece of thin plate. According to the chromatographic conditions to spread, take out, dry and color. Cover it with the same size of glass plate and seal it for four cycles. 10min later, scan it under thin layer scanning. λS = 535nm, λR = 650nm; dual wavelength reflection zigzag scanning; slit: 1.25mm × 1.25mm; sensitivity × 5. Measure the absorption integral value of the sample and reference substance, and calculate the content by two external standard method. 5. Measurement results: Based on the above-mentioned conditions, the content of triptolide in Tripterygium root bark, root center and whole root were 0.001%, 0.0004%, 0.0018%.

Biological Activity

Inhibits cytokine-induced gene expression via inhibition of NF- κ B transcriptional activity. Induces apoptosis in tumor cells by blocking TNF- α mediated c-IAP2 and c-IAP1 (members of the inhibitor of apoptosis family) induction. Immunosuppressive with anti-inflammatory and antitumor activity.

Biochem/physiol Actions

Triptolide is a diterpene triepoxide, the principal active ingredient in extracts from the Chinese herb Tripterygium wilfordii hook (TwHF). It is a potent immunosuppressant and anti-inflammatory. Triptolide has been shown to inhibit the expression of IL-2 in activated T cells at the level of purine-box/nuclear factor and NF-κB mediated transcription activation. It synergizes with cyclosporin A in promoting graft survival in animal models and in suppression of graft versus host disease in allogeneic bone marrow transplants. In addition, it induces apoptosis in tumor cells and potentiates tumor necrosis factor (TNFα) induction of apoptosis in part through the suppression of c-IAP2 and c-IAP1 induction.

References

1) He?et al. (2015),?Covalent Modification of a Cysteine Residue in the XPB Subunit of the General Transcription Factor TFIIH Through Single Epoxide Cleavage of the Transcription Inhibitor Triptolide; Angew. Chem. Int. Ed. Eng.?54?1859 2) Lee?et al. (1999),?PG490 (Triptolide) Cooperates with Tumor Necrosis factor-α to Induce Apoptosis in Tumor Cells; J. Biol. Chem,?274?13451 3) Qiao?et al. (2016),?Synergistic antitumor activity of gemcitabine combined with triptolide in pancreatic cancer cells; Oncol. Lett.,?11?3527 4) Fan?et al.?(2016),?Triptolide Modulates TREM-1 Signal Pathway to Inhibit the Inflammatory Response in Rheumatoid Arthritis; Int. J. Mol. Sci.?17?498

InChI:InChI=1/C20H24O6/c1-8(2)18-13(25-18)14-20(26-14)17(3)5-4-9-10(7-23-15(9)21)11(17)6-12-19(20,24-12)16(18)22/h8,11-14,16,22H,4-7H2,1-3H3/t11-,12-,13-,14-,16+,17-,18-,19+,20+/m0/s1

Upstream product

• 38647-11-9 l-triptonide 
• 925-90-6 ethylmagnesium bromide 
• 216440-77-6 C₂₀H₂₂O₅ 
• 225786-93-6 (3bR,9bS)-7-Isopropyl-6-methoxy-9b-methyl-3,3b,4,9b,10,11-hexahydro-phenanthro[1,2-c]furan-1,5-dione 
• 79548-61-1 (3bR,9bS)-6-hydroxy-7-isopropyl-9b-methyl-3b,4,10,11-tetrahydrophenanthro[1,2-c]furan-1,5(3H,9bH)-dione 
• 225787-03-1 (5R,6S,8R,9S)-3-Isopropyl-9-methyl-7,8,9,11,12,15-hexahydro-6H-16,20-dioxa-cyclopropa[5,6]cyclopenta[a]phenanthrene-4,17-dione 
• 74709-24-3 7β,14,19-trihydroxy-18(4->3)abeo-abieta-3,8,11,13-tetraen-18-oic acid lactone 

Downstream Products

• 38647-11-9 l-triptonide 
• 847440-49-7 triptolide methylthiomethyl ether 
• 1254702-92-5 14-O-phosphonooxymethyltriptolide dibenzyl ester 
• 195883-06-8 4-(((5bS,6aS,7aR,8R,8aS,9aS,9bS,10aS,10bS)-8a-isopropyl-10b-methyl-3-oxo-1,2,3,5,5b,6,6a,8,8a,9a,9b,10b-dodecahydrotris(oxireno)[2',3':4b,5;2'',3'':6,7;2''',3''':8a,9]phenanthro[1,2-c]furan-8-yl)oxy)-4-oxobutanoic acid 
• 883976-18-9 C₂₀H₂₄O₅ 
• 139713-80-7 16-hydroxytriptolide 
• 99694-86-7 15-hydroxyltriptolide 
• 38647-10-8 triptodiolide 
• 583028-68-6 5α-hydroxytriptolide 

Relevant articles and documents

Partial synthesis of 14-deoxy-14-aminotriptolide

Triptolide is a diterpene triepoxide isolated from Tripterygium wilfordii, a Chinese medicinal plant and possessing a wealth of biological activities. In order to produce more soluble derivatives of triptolide, its 14-amino analogue was prepared. Initial attempts at its preparation using classical displacements led to rearranged compounds and success was finally met using carefully controlled Borch conditions. 14-Deoxy-14-aminotriptolide was thus prepared for the first time and it was found 10 times less cytotoxic than the parent compound.

Semisynthesis of triptolide analogues: Effect of B-ring substituents on cytotoxic activities

A series of B-ring modified analogues of triptolide were synthesized and tested for their cytotoxicity against two human tumor cell lines (U251 and PC-3). From the current investigation, the structure-cytotoxic activity relationships of these analogues su

Semisynthesis of triptolide analogues: Effect of γ-lactone and C-14 substituents on cytotoxic activities

Triptolide γ-lactone and C-14 analogues were prepared and evaluated cytotoxity against human lung adenocarcinoma epithelial A549 cells and human colon adenocarcinoma HT-29 cells. γ-Lactone substructure and C-14 substituents affected the biological activities significantly.

TRIPTOLIDE PRODRUGS

The invention provides compounds of formula (I): or a salt thereof. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods using the compounds of formula I.

Efficient syntheis of the key intermediate triptophenolide methyl ether for the synthesis of(-)-triptolide

An efficient synthesis of triptophenolide methyl ether 4 from the readily available abietic acid 3 in nine steps is described and successfully applied to the synthesis of (-)-triptolide 1.The route is of characteristic of low cost, high yield and easy operation.In addition, every reaction in this route has been successfully scaled-up to a 100 g substrate level without loss of yield.

Semisynthesis of C-ring modified triptolide analogues and their cytotoxic activities

Several C-ring modified analogues of a potent antileukemic diterpene, triptolide (1), were synthesized and their structure-activity relationships were studied.

Cytotoxic Biotransformed Products from Triptonide by Aspergillus niger

The diterpenoid triepoxides are the major active constituents of Tripterygium wilfordii with potent antitumor and immune activities. But the strong toxicity of these compounds has restricted their application to a great extent. In order to find more effective compounds with less toxicity, structural modifications of triptonide (1) by Aspergillus niger (AS 3.739) were investigated and four biotransformed products were obtained. Based on their chemical and spectral data, their structures were elucidated as 5α-hydroxytriptonide (2), triptolide (3), 17-hydroxytriptonide (4), and 16-hydroxytriptonide (5), among which 2, 4 and 5 are new compounds. All the three new transformed products showed cytotoxic activities against the majority of the human tumor cell lines tested, however, they are found to possess less cytotoxic activity when compared with 1. Both compounds 4 and 5 showed similar cytotoxic activity and their IC50 values were 5-15 fold less than 1, while 2 is about 100 times less active than 1.

Enantioselective Total Synthesis of (-)-Triptolide, (-)-Triptonide, (+)-Triptophenolide, and (+)-Triptoquinonide

The first enantioselective total synthesis of (-)-triptolide (1), (-)-triptonide (2), (+)-triptophenolide (3), and (+)-triptoquinonide (4) was completed. The key step involves lanthanide triflate-catalyzed oxidative radical cyclization of (+)-8-phenylmenthyl ester 30 mediated by Mn(OAc)9, providing intermediate 31 with good chemical yield (77%) and excellent diastereoselectivity (dr 38:1). (+)-Triptophenolide methyl ether (5) was then prepared in >99% enantiomeric excess (>99% ee), and readily converted to natural products 1-4. In addition, transition state models were proposed to explain the opposite chiral induction observed in the oxidative radical cyclization reactions of chiral β-keto esters 17 (without an α-substituent) and 17a (with an α-chloro substituent).

Immunosuppressive compounds and methods

Compounds and methods for use in immunosuppressive and anti-inflammatory treatment are described. The compounds are triptolide analogs with improved water solubility and low toxicity.