Triptolide

Triptolide
Identifiers
38748-32-2
Properties
C20H24O6
Molar mass 360.41 g·mol−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 found in the Thunder God Vine, Tripterygium wilfordii. It has in vitro and in vivo activities against mouse models of polycystic kidney disease[1] and pancreatic cancer, but its physical properties limit its therapeutic potential.[2] Consequently, a synthetic prodrug, minnelide, is being studied clinically instead.[2]

Mechanism of action

Several putative target proteins of triptolide have been reported, including polycystin-2,[3] ADAM10,[4] DCTPP1,[5] TAB1,[6] and XPB.[7][8] Multiple triptolide-resistant mutations exist in XPB (ERCC3) and its partner protein GTF2H4.[9] 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.[7] The level of resistance conferred by the C342T mutation is about 100-fold higher than the most triptolide-resistant mutants previously identified.[9] Together, these results validate XPB as a target responsible for the antiproliferative activity of triptolide.

Minnelide

Minnelide is a more water-soluble analog of triptolide, and in-vivo (in the presence of phosphates) it is converted to triptolide.[10][2] In a mouse model of pancreatic cancer it was "even more effective than gemcitabine". Phase 1 clinical trial planned for Dec 2012.[10]

References

  1. ↑ 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.
  2. 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.
  3. ↑ 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;
  4. ↑ 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;
  5. ↑ T. W. Corson, H. Cavga, N. Aberle, C. M. Crews, Triptolide directly inhibits dCTP pyrophosphatase. Chembiochem 2011, 12, 1767-1773;
  6. ↑ 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.
  7. 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
  8. ↑ 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.
  9. 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
  10. 1 2 Thunder God Vine Drug Zaps Pancreatic Cancer. GenEng. 2012
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