Triptolide

Triptolide
Identifiers
38748-32-2
ECHA InfoCard 100.208.723
Properties
C20H24O6
Molar mass 360.41 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

Triptolide is a diterpenoid epoxide which is endogenously 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 limit its therapeutic potential.[3] Consequently, a synthetic prodrug, minnelide, is being studied clinically instead.[3] Due to its low solubility in water, several water-soluble analogs have been formulated, including Minnelide, which is currently in Phase I clinical trials.[4]

Mechanism of action

Several putative target proteins of triptolide have been reported, including polycystin-2,[5] ADAM10,[6] DCTPP1,[7] TAB1,[8] and XPB.[9][10] Multiple triptolide-resistant mutations exist in XPB (ERCC3) and its partner protein GTF2H4.[11] 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.[9] The level of resistance conferred by the C342T mutation is about 100-fold higher than the most triptolide-resistant mutants previously identified.[11] Together, these results validate XPB as a target responsible for the antiproliferative activity of triptolide.

Water-soluble prodrugs

Minnelide is a more water-soluble analog of triptolide, and in-vivo (in the presence of phosphates) it is converted to triptolide.[3][12] In a mouse model of pancreatic cancer it was "even more effective than gemcitabine". Phase 1 clinical trial planned for Dec 2012.[12]

Glutriptolide 2, a glucose conjugate of triptolide with better solubility and lower toxicity, did not inhibit XPB activity in vitro, but exhibited remarkable tumor control in vivo, which is likely due to sustained stepwise release of active triptolide within cancer cells. And the preclinical research of Glucotriptolide 2 was on the way by Rapafusyn Pharmaceuticals[13]

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; Gurvich, Vadim J.; Georg, Gunda I. (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.
  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. Retrieved 18 October 2012.
  3. 1 2 3 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. Retrieved 18 October 2012.
  4. ↑ "Study of Minnelide in Patients With Advanced GI Tumors". Retrieved 6 October 2016.
  5. ↑ 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;
  6. ↑ 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;
  7. ↑ T. W. Corson, H. Cavga, N. Aberle, C. M. Crews, Triptolide directly inhibits dCTP pyrophosphatase. Chembiochem 2011, 12, 1767-1773;
  8. ↑ 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.
  9. 1 2 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
  10. ↑ 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.
  11. 1 2 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
  12. 1 2 Thunder God Vine Drug Zaps Pancreatic Cancer. GenEng. 2012
  13. ↑ Q.L. He, I. Minn, Q. Wang, P. Xu, S. A. Head, E. Datan, B.Yu, M. G. Pomper, and J. O. Liu Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation, http://onlinelibrary.wiley.com/doi/10.1002/ange.201606121/abstract Angew. Chem. Int. Ed. 2016, 55, 12035 –12039
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