雷公藤內酯

化合物

雷公藤內酯(英語:Triptolide)是一個二萜環氧化物,它由雷公藤(學名:Tripterygium wilfordii)產生。 它在體外實驗和體內實驗中對小鼠模型多囊腎病[2]胰腺癌具有抗癌作用,但是其物理性質[3]和嚴重的毒性[4]限制了它的治療潛力。

雷公藤內酯
識別
CAS號 38748-32-2
PubChem 107985
ChemSpider 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
ChEBI 9747
KEGG C09204
性質
化學式 C20H24O6
摩爾質量 360.4 g·mol−1
溶解性 0.017 mg/mL[1]
若非註明,所有數據均出自標準狀態(25 ℃,100 kPa)下。

因此,合成的水溶性前體藥物Minnelide正在進行臨床上的研究。[5]

作用機理

幾個可能的雷公藤內脂的目標蛋白質已經被報告出來,包括polycystin-2[6]ADAM10[7]DCTPP1[8]TAB1[9]XPB[10]多雷公藤抗性基因突變中存在XPB(ERCC3)及其協同的蛋白質 GTF2H4[11]然而,沒有雷公藤抗性基因突變也在 polycystin-2ADAM10DCTPP1TAB1中被發現。 XPBCys342被認定為經由雷公藤內酯的12,13-環氧化物基團進行共價修飾的殘基,而XPB-C342T突變呈現的T7115細胞系幾乎完全耐受雷公藤內酯。[12]由C342T突變導致的耐受水平是之前確定的大多數雷公藤內酯耐受突變的約100倍。 綜上所述,這些結果說明XPB是雷公藤內酯影響細胞增殖活動的目標。

水溶性的前體藥物

Minnelide是一種由人工合成,具有更好的水溶性的雷公藤內酯類似物,它可以在體內轉化為雷公藤內酯。[13]在臨床前期的小鼠模型胰腺癌中,他的表現比吉西他濱更有效。臨床一期研究計劃於2012年展開。

糖化雷公藤甲素是一種葡萄糖與雷公藤內酯合成的化合物,具有更好的溶解性以及更低的毒性。它在體外實驗中並沒有抑制XPB的活性,但在體內實驗中被發現有抗癌活性,這可能是雷公藤內酯在癌細胞內持續逐步被釋放出來的緣故。[14]

參考文獻

  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. Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts. Journal of Medicinal Chemistry. 10 December 2015, 58 (23): 9334–9344. PMC 4678411 . PMID 26596892. doi:10.1021/acs.jmedchem.5b01329. 
  2. ^ Leuenroth, Stephanie. Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. PNAS. 2007, 104 (11): 4389–4394 [18 October 2012]. PMC 1838612 . PMID 17360534. doi:10.1073/pnas.0700499104. (原始內容存檔於2017-11-20). 
  3. ^ Chugh, Rohit. A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer. Science Translational Medicine. 2012, 4 (156): 156ra139 [18 October 2012]. PMC 3656604 . PMID 23076356. doi:10.1126/scitranslmed.3004334. (原始內容存檔於2021-05-26). 
  4. ^ Liu Q. Triptolide and its expanding multiple pharmacological functions. International Immunopharmacology. 2011, 11 (3): 377–383. PMID 21255694. doi:10.1016/j.intimp.2011.01.012. 
  5. ^ Study of Minnelide in Patients With Advanced GI Tumors. [6 October 2016]. (原始內容存檔於2021-04-20). 
  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. ^ 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. ^ 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. ^ 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
  13. ^ Thunder God Vine Drug Zaps Pancreatic Cancer. GenEng. 2012. [2018-02-01]. (原始內容存檔於2018-06-24). 
  14. ^ He, Qing-Li; Minn, Il; Wang, Qiaoling; Xu, Peng; Head, Sarah A; Datan, Emmanuel; Yu, Biao; Pomper, Martin G; Liu, Jun O. Targeted Delivery and Sustained Antitumor Activity of Triptolide through Glucose Conjugation. Angewandte Chemie. 2016, 128 (39): 12214. doi:10.1002/ange.201606121.