雷公藤内酯

雷公藤内酯
识别
CAS号	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
性质
化学式	C20H24O6
摩尔质量	360.4 g·mol−1
溶解性（水）	0.017 mg/mL
	若非注明，所有数据均出自标准状态（25 ℃，100 kPa）下。

雷公藤内酯（英語：Triptolide）是一个二萜类环氧化物，它由雷公藤（学名：Tripterygium wilfordii）产生。它在体外实验和体内实验中对小鼠模型的多囊肾病^[2]和胰腺癌具有抗癌作用，但是其物理性质^[3]和严重的毒性^[4]限制了它的治疗潜力。

因此，合成的水溶性前体药物Minnelide正在进行临床上的研究。^[5]

作用机理

几个可能的雷公藤内脂的目标蛋白质已经被报告出来，包括polycystin-2、^[6]ADAM10、^[7]DCTPP1、^[8]TAB1、^[9]和XPB。^[10]多雷公藤抗性基因突变中存在XPB(ERCC3)及其协同的蛋白质 GTF2H4。^[11]然而，没有雷公藤抗性基因突变也在 polycystin-2、ADAM10、DCTPP1和TAB1中被发现。 XPB的Cys342被认定为经由雷公藤内酯的12,13-环氧化物基团进行共价修饰的残基，而XPB-C342T突变呈现的T7115细胞系几乎完全耐受雷公藤内酯。^[12]由C342T突变导致的耐受水平是之前确定的大多数雷公藤内酯耐受突变的约100倍。综上所述，这些结果说明XPB是雷公藤内酯影响细胞增殖活动的目标。

水溶性的前体药物

Minnelide是一种由人工合成，具有更好的水溶性的雷公藤内酯类似物，它可以在体内转化为雷公藤内酯。^[13]在临床前期的小鼠模型胰腺癌中，他的表现比吉西他滨更有效。临床一期研究计划于2012年展开。

糖化雷公藤甲素是一种葡萄糖与雷公藤内酯合成的化合物，具有更好的溶解性以及更低的毒性。它在体外实验中并没有抑制XPB的活性，但在体内实验中被发现有抗癌活性，这可能是雷公藤内酯在癌细胞内持续逐步被释放出来的缘故。^[14]

参考文献

^ 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.
^ 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. （原始内容存档于2017-11-20）.
^ 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. （原始内容存档于2021-05-26）.
^ 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.
^ Study of Minnelide in Patients With Advanced GI Tumors. [6 October 2016]. （原始内容存档于2021-04-20）.
^ 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;
^ 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;
^ T. W. Corson, H. Cavga, N. Aberle, C. M. Crews, Triptolide directly inhibits dCTP pyrophosphatase. Chembiochem 2011, 12, 1767-1773;
^ 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.
^ 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.
^ 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
^ 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
^ Thunder God Vine Drug Zaps Pancreatic Cancer. GenEng. 2012. [2018-02-01]. （原始内容存档于2018-06-24）.
^ 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.

[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. （原始内容存档于2017-11-20）.

[Chugh-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. （原始内容存档于2021-05-26）.

[Liu2011-4] 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]. （原始内容存档于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.

[feng2014-11] 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

[Liu2015-12] 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

[GN-min-2012-13] Thunder God Vine Drug Zaps Pancreatic Cancer. GenEng. 2012. [2018-02-01]. （原始内容存档于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.

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