Triptolide

Last updated
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
ECHA InfoCard 100.208.723 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=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
    Key: DFBIRQPKNDILPW-CIVMWXNOSA-N
  • 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
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).

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]

Contents

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 Minnelide structure.png
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]

Related Research Articles

<i>Tripterygium wilfordii</i> Species of flowering plant

Tripterygium wilfordii, or léi gōng téng (Mandarin), sometimes called thunder god vine but more properly translated thunder duke vine, is a vine used in traditional Chinese medicine.

<span class="mw-page-title-main">Endostatin</span>

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<span class="mw-page-title-main">XPB</span> Mammalian protein found in Homo sapiens

XPB is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex.

Transcription factor II H (TFIIH) is an important protein complex, having roles in transcription of various protein-coding genes and DNA nucleotide excision repair (NER) pathways. TFIIH first came to light in 1989 when general transcription factor-δ or basic transcription factor 2 was characterized as an indispensable transcription factor in vitro. This factor was also isolated from yeast and finally named TFIIH in 1992.

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<span class="mw-page-title-main">Epoxide hydrolase 2</span> Protein-coding gene in the species Homo sapiens

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Small molecule drug conjugates or SMDCs are built with three modules: a targeting ligand, a linker and a drug payload. The targeting ligands consist of low molecular weight, high-affinity ligands that are precisely linked to potent drugs. The linkers are designed to be stable in the bloodstream and then release the active drug from the targeting ligand when the SMDC is taken up by the diseased cell. The drug payloads are highly active molecules that are too toxic to be administered in their untargeted forms at therapeutic dose levels. This modular approach allows varying targeting ligands, linker systems and drug payloads and generate SMDCs for different diseases. The most advanced SMDC is vintafolide, a derivative of the anti-mitotic chemotherapy drug vinblastine which is chemically linked to folic acid. Potent, bioactive natural products like triptolide that inhibit mammalian transcription has been recently reported as a glucose conjugate for targeting hypoxic cancer cells with increased glucose transporter expression.

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Tellimagrandin I is an ellagitannin found in plants, such as Cornus canadensis, Eucalyptus globulus, Melaleuca styphelioides, Rosa rugosa, and walnut. It is composed of two galloyl and one hexahydroxydiphenyl groups bound to a glucose residue. It differs from Tellimagrandin II only by a hydroxyl group instead of a third galloyl group. It is also structurally similar to punigluconin and pedunculagin, two more ellagitannin monomers.

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. PMC   4678411 . PMID   26596892.
  2. ↑ Leuenroth, Stephanie (2007). "Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease". PNAS. 104 (11): 4389–4394. Bibcode:2007PNAS..104.4389L. doi: 10.1073/pnas.0700499104 . PMC   1838612 . PMID   17360534.
  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. PMC   3656604 . 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" . Retrieved 6 October 2016.
  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. 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
  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. 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
  13. ↑ Noel, Pawan; Hussein, Shaimaa; Ng, Serina; Antal, Corina E.; Lin, Wei; Rodela, Emily; Delgado, Priscilla; Naveed, Sanna; Downes, Michael; Lin, Yin; Evans, Ronald M.; Von Hoff, Daniel D.; Han, Haiyong (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 . PMC   7653036 . 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". ClinicalTrials.gov. Retrieved 13 March 2018.
  16. ↑ He, Qing-Li; Minn, Il; Wang, Qiaoling; Xu, Peng; Head, Sarah A; Datan, Emmanuel; Yu, Biao; Pomper, Martin G; Liu, Jun O (2016). "Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation". Angewandte Chemie. 128 (39): 12214. Bibcode:2016AngCh.12812214H. doi:10.1002/ange.201606121.
  17. ↑ Datan E, Minn I, Peng X, He QL, Ahn H, Yu B, Pomper MG, Liu JO (2020). "A Glucose-Triptolide Conjugate Selectively Targets Cancer Cells under Hypoxia". iScience. 23 (9): 101536. Bibcode:2020iSci...23j1536D. doi: 10.1016/j.isci.2020.101536 . PMC   7509213 . PMID   33083765.
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