Triptolide

{{distinguish|text = Triptonide, another derivative of ''Tripterygium wilfordii''}} {{Chembox | ImageFile = Triptolide.svg | ImageSize = 200px | ImageAlt = | PIN = (3b''S'',4a''S'',5a''S'',6''R'',6a''R'',7a''S'',7b''S'',8a''S'',9b''S'')-6-Hydroxy-8b-methyl-6a-(propan-2-yl)-3b,4,4a,5a,6,6a,7a,7b,8a,8b,9,10-dodecahydrotris(oxireno)[2′,3′:4b,5;2′′,3′′:6,7;2′′′,3′′′:8a,9]phenanthro[1,2-''c'']furan-1(3''H'')-one | OtherNames = |Section1={{Chembox Identifiers | CASNo = 38748-32-2 | CASNo_Ref = {{cascite|correct|CAS}} | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 19ALD1S53J | PubChem = 107985 | ChemSpiderID = 97099 | SMILES = CC(C)[C@@]12[C@@H](O1)[C@H]3[C@@]4(O3)[C@]5(CCC6=C([C@@H]5C[C@H]7[C@]4([C@@H]2O)O7)COC6=O)C | StdInChI = 1S/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 | StdInChIKey = DFBIRQPKNDILPW-CIVMWXNOSA-N | ChEBI = 9747 | KEGG = C09204}} |Section2={{Chembox Properties | C=20 | H=24 | O=6 | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = 0.017 mg/mL<ref>{{cite journal|last1=Patil|first1=Satish|last2=Lis|first2=Lev G.|last3=Schumacher|first3=Robert J.|last4=Norris|first4=Beverly J.|last5=Morgan|first5=Monique L.|last6=Cuellar|first6=Rebecca A. D.|last7=Blazar|first7=Bruce R.|last8=Suryanarayanan|first8=Raj|last9=Gurvich|first9=Vadim J.|last10=Georg|first10=Gunda I.|title=Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts|journal=Journal of Medicinal Chemistry|date=10 December 2015|volume=58|issue=23|pages=9334–9344|doi=10.1021/acs.jmedchem.5b01329|pmid=26596892|pmc=4678411}}</ref> }} |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }}

'''Triptolide''' is a diterpenoid epoxide which is produced by the thunder god vine, ''Tripterygium wilfordii''. It has ''in vitro'' and ''in vivo'' activities against mouse models of polycystic kidney disease<ref>{{cite journal |last=Leuenroth |first=Stephanie |year=2007 |title=Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease |journal=PNAS |volume=104 |issue=11 |pages=4389–4394 |doi=10.1073/pnas.0700499104 |pmid=17360534 |pmc=1838612|bibcode=2007PNAS..104.4389L |doi-access=free }}</ref> and pancreatic cancer, but its physical properties<ref name=Chugh>{{cite journal |last=Chugh |first=Rohit |year=2012 |title=A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer |journal=Science Translational Medicine |volume=4 |issue=156 |pages=156ra139 |doi=10.1126/scitranslmed.3004334 |pmid=23076356 |pmc=3656604 |url=}}</ref> and severe toxicity<ref name=Liu2011>{{cite journal |author=Liu Q. |title=Triptolide and its expanding multiple pharmacological functions |journal=International Immunopharmacology |year=2011 |volume=11 |issue=3 |pages=377–383 |pmid=21255694 |doi=10.1016/j.intimp.2011.01.012}}</ref> limit its therapeutic potential. Consequently, a synthetic water-soluble prodrug, minnelide, is being studied clinically instead.<ref name=Chugh/><ref>{{cite web|title=Study of Minnelide in Patients With Advanced GI Tumors|url=https://clinicaltrials.gov/ct2/show/NCT01927965|access-date=6 October 2016}}</ref>

Triptolide is a component of ContraPest, a contraceptive pest control liquid used to reduce rat populations in the United States.

==Mechanism of action== Several putative target proteins of triptolide have been reported, including polycystin-2,<ref>S. J. Leuenroth, D. Okuhara, J. D. Shotwell, G. S. Markowitz, Z. Yu, S. Somlo, C. M. Crews, Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. ''Proc Natl Acad Sci U S A'' 2007, 104, 4389-4394;</ref> ADAM10,<ref>R. Soundararajan, R. Sayat, G. S. Robertson, P. A. Marignani,Triptolide: An inhibitor of a disintegrin and metalloproteinase 10 (ADAM10) in cancer cells. ''Cancer Biol Ther'' 2009, 8, 2054-2062;</ref> DCTPP1,<ref>T. W. Corson, H. Cavga, N. Aberle, C. M. Crews, Triptolide directly inhibits dCTP pyrophosphatase. ''ChemBioChem'' 2011, 12, 1767-1773;</ref> TAB1,<ref>Y. Lu, Y. Zhang, L. Li, X. Feng, S. Ding, W.Zheng, J. Li, P. Shen,TAB1: A Target of Triptolide in Macrophages. ''Chem. Biol.'' 2014, 21, 246 – 256.</ref> and XPB.<ref name=Liu2015 /><ref>D. V. Titov, B. Gilman, Q. L.He, S. Bhat,W. K. Low, Y. Dang,M.Smeaton, A. L. Demain, P. S. Miller, J. F. Kugel, J. A. Goodrich,J. O. Liu, XPB, a subunit of TFIIH, is a target of the natural product triptolide. ''Nat. Chem. Biol.'' 2011, 7, 182 – 188.</ref> Multiple triptolide-resistant mutations exist in XPB (ERCC3) and its partner protein GTF2H4.<ref name=feng2014>Y. Smurnyy, M. Cai, H. Wu, E. McWhinnie, J. A. Tallarico, Y.Yang, Y. Feng, DNA sequencing and CRISPR-Cas9 gene editing for target validation in mammalian cells. ''Nat. Chem. Biol''. 2014, 10, 623 – 625</ref> However, no triptolide-resistant mutations were found in polycystin-2, ADAM10, DCTPP1 and TAB1. Cys342 of XPB was identified as the residue that undergoes covalent modification by the 12,13-epoxide group of triptolide, and the XPB-C342T mutant rendered the T7115 cell line nearly completely resistant to triptolide.<ref name=Liu2015>Q. L. He, D. V. Titov, J. Li, M. Tan, Z. Ye, Y. Zhao, D. Romo, and J. O. Liu. 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.'' 2015, 54, 1859 –1863</ref> The level of resistance conferred by the C342T mutation is about 100-fold higher than the most triptolide-resistant mutants previously identified.<ref name=feng2014 /> Together, these results validate XPB as a target responsible for the antiproliferative activity of triptolide. The disruption of super-enhancer networks has also been suggested as a mechanism of action.<ref>{{cite journal |last1=Noel |first1=Pawan |last2=Hussein |first2=Shaimaa |last3=Ng |first3=Serina |last4=Antal |first4=Corina E. |last5=Lin |first5=Wei |last6=Rodela |first6=Emily |last7=Delgado |first7=Priscilla |last8=Naveed |first8=Sanna |last9=Downes |first9=Michael |last10=Lin |first10=Yin |last11=Evans |first11=Ronald M. |last12=Von Hoff |first12=Daniel D. |last13=Han |first13=Haiyong |title=Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts |journal=Oncogenesis |date=9 November 2020 |volume=9 |issue=11 |page=100 |doi=10.1038/s41389-020-00285-9|pmid=33168807 |pmc=7653036 |doi-access=free }}</ref>

==Water-soluble prodrugs== Minnelide is a more water-soluble synthetic prodrug of triptolide which is converted to triptolide ''in vivo''.<ref name=Chugh/><ref name=GN-min-2012>[http://www.genengnews.com/gen-news-highlights/thunder-god-vine-drug-zaps-pancreatic-cancer/81247498/ Thunder God Vine Drug Zaps Pancreatic Cancer. GenEng. 2012]</ref> In a preclinical mouse model of pancreatic cancer, it was "even more effective than gemcitabine". Its Phase II clinical trials are expected to conclude in February 2019.<ref>{{cite web|title=A Phase II, International Open Label Trial of Minnelide in Patients With Refractory Pancreatic Cancer|url=https://clinicaltrials.gov/ct2/show/NCT03117920|website=ClinicalTrials.gov|access-date=13 March 2018|language=en}}</ref>{{update inline|date=December 2025}} :220px|thumb|left|Minnelide{{clear-left}} Glutriptolide, a glucose conjugate of triptolide with better solubility and lower toxicity, did not inhibit XPB activity ''in vitro'', but exhibited tumor control ''in vivo'', which is likely due to sustained stepwise release of active triptolide within cancer cells.<ref>{{cite journal | doi = 10.1002/ange.201606121| title = Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation| journal = Angewandte Chemie| volume = 128| issue = 39| pages = 12214| year = 2016| last1 = He| first1 = Qing-Li| last2 = Minn| first2 = Il| last3 = Wang| first3 = Qiaoling| last4 = Xu| first4 = Peng| last5 = Head| first5 = Sarah A| last6 = Datan| first6 = Emmanuel| last7 = Yu| first7 = Biao| last8 = Pomper| first8 = Martin G| last9 = Liu| first9 = Jun O| bibcode = 2016AngCh.12812214H}}</ref> A second generation glutriptolide has been recently reported for targeting hypoxic cancer cells with increased glucose transporter expression.<ref>{{cite journal | journal = iScience | title = A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia | volume = 23 | issue = 9 | year = 2020 |vauthors=Datan E, Minn I, Peng X, He QL, Ahn H, Yu B, Pomper MG, Liu JO | article-number = 101536 | pmid = 33083765 | doi=10.1016/j.isci.2020.101536| pmc = 7509213 | bibcode = 2020iSci...23j1536D | doi-access = free }}</ref>

==References== {{reflist|2}}

Category:Diterpenes Category:Epoxides Category:Furanones Category:Secondary alcohols Category:Isopropyl compounds Category:Plant toxins