Chemistry:Triptolide

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Triptolide
Triptolide.svg
Names
Preferred IUPAC name
(3bS,4aS,5aS,6R,6aR,7aS,7bS,8aS,9bS)-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(3H)-one
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
UNII
Properties
C20H24O6
Molar mass 360.406 g·mol−1
0.017 mg/mL[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Tracking categories (test):

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[2] and pancreatic cancer, but its physical properties[3] and severe toxicity[4] limit its therapeutic potential. Consequently, a synthetic water-soluble prodrug, minnelide, is being studied clinically instead.[3][5]

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,[6] ADAM10,[7] DCTPP1,[8] TAB1,[9] and XPB.[10][11] Multiple triptolide-resistant mutations exist in XPB (ERCC3) and its partner protein GTF2H4.[12] 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.[10] The level of resistance conferred by the C342T mutation is about 100-fold higher than the most triptolide-resistant mutants previously identified.[12] 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.[13]

Water-soluble prodrugs

Minnelide is a more water-soluble synthetic prodrug of triptolide which is converted to triptolide in vivo.[3][14] 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.[15]

Minnelide

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.[16] A second generation glutriptolide has been recently reported for targeting hypoxic cancer cells with increased glucose transporter expression.[17]

References

  1. ↑ Patil, Satish; Lis, Lev G.; Schumacher, Robert J.; Norris, Beverly J.; Morgan, Monique L.; Cuellar, Rebecca A. D.; Blazar, Bruce R.; Suryanarayanan, Raj et al. (10 December 2015). "Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts". Journal of Medicinal Chemistry 58 (23): 9334–9344. doi:10.1021/acs.jmedchem.5b01329. PMID 26596892. 
  2. ↑ Leuenroth, Stephanie (2007). "Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease". PNAS 104 (11): 4389–4394. doi:10.1073/pnas.0700499104. PMID 17360534. Bibcode: 2007PNAS..104.4389L. 
  3. ↑ 3.0 3.1 3.2 Chugh, Rohit (2012). "A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer". Science Translational Medicine 4 (156): 156ra139. doi:10.1126/scitranslmed.3004334. PMID 23076356. 
  4. ↑ Liu Q. (2011). "Triptolide and its expanding multiple pharmacological functions". International Immunopharmacology 11 (3): 377–383. doi:10.1016/j.intimp.2011.01.012. PMID 21255694. 
  5. ↑ "Study of Minnelide in Patients With Advanced GI Tumors". https://clinicaltrials.gov/ct2/show/NCT01927965. 
  6. ↑ 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;
  7. ↑ 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;
  8. ↑ T. W. Corson, H. Cavga, N. Aberle, C. M. Crews, Triptolide directly inhibits dCTP pyrophosphatase. ChemBioChem 2011, 12, 1767-1773;
  9. ↑ 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.
  10. ↑ 10.0 10.1 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
  11. ↑ 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.
  12. ↑ 12.0 12.1 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
  13. ↑ Noel, Pawan; Hussein, Shaimaa; Ng, Serina; Antal, Corina E.; Lin, Wei; Rodela, Emily; Delgado, Priscilla; Naveed, Sanna et al. (9 November 2020). "Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts". Oncogenesis 9 (11): 100. doi:10.1038/s41389-020-00285-9. PMID 33168807. 
  14. ↑ Thunder God Vine Drug Zaps Pancreatic Cancer. GenEng. 2012
  15. ↑ "A Phase II, International Open Label Trial of Minnelide in Patients With Refractory Pancreatic Cancer" (in en). https://clinicaltrials.gov/ct2/show/NCT03117920. 
  16. ↑ He, Qing-Li; Minn, Il; Wang, Qiaoling; Xu, Peng; Head, Sarah A; Datan, Emmanuel; Yu, Biao; Pomper, Martin G et al. (2016). "Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation". Angewandte Chemie 128 (39): 12214. doi:10.1002/ange.201606121. Bibcode: 2016AngCh.12812214H. 
  17. ↑ "A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia". iScience 23 (9): 101536. 2020. doi:10.1016/j.isci.2020.101536. PMID 33083765. Bibcode: 2020iSci...23j1536D. 



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