卡莫氟

化合物

卡莫氟INN:Carmofur)或HCFU(1-hexylcarbamoyl-5-fluorouracil)是一种嘧啶类似物,用作抗肿瘤剂。它是氟尿嘧啶的衍生物,是可口服给药的氟尿嘧啶的亲脂性掩蔽类似物。[1]

卡莫氟
临床资料
其他名称1-hexylcarbamoyl-5-fluorouracil, HCFU, N-hexylcarbamoyl-5-fluorouracil, Yamaful, NCGC00095165-01, Hexylcarbamoyl fluorouracil, 61422-45-5, UNII-HA82M3RAB2, CCRIS 2759, C11H16FN3O3, Uracil, 5-fluoro-1-hexylcarbamoyl-, BRN 0888898, HA82M3RAB2, 1(2H)-Pyrimidinecarboxamide, 5-fluoro-N-hexyl-3,4,
AHFS/Drugs.com国际药品名称
给药途径Oral
ATC码
识别信息
  • 5-fluoro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide
CAS号61422-45-5  checkY
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard英语CompTox Chemicals Dashboard (EPA)
ECHA InfoCard100.216.315 编辑维基数据链接
化学信息
化学式C11H16FN3O3
摩尔质量257.27 g·mol−1
3D模型(JSmol英语JSmol
  • CCCCCCNC(=O)N1C=C(C(=O)NC1=O)F
  • InChI=1S/C11H16FN3O3/c1-2-3-4-5-6-13-10(17)15-7-8(12)9(16)14-11(15)18/h7H,2-6H2,1H3,(H,13,17)(H,14,16,18) ☒N
  • Key:AOCCBINRVIKJHY-UHFFFAOYSA-N ☒N

生物学

编辑

卡莫氟前药在肠道中被摄入和吸收,克服了二氢嘧啶脱氢酶降解氟尿嘧啶的问题。一旦进入细胞,卡莫氟前药就会转化为氟尿嘧啶。

作用机制

编辑

卡莫氟前药的作用机制传统上被认为是产生氟尿嘧啶。[2]然而,卡莫氟是一种高效的酸性神经酰胺酶AC)抑制剂。[2]神经酰胺影响癌细胞的存活、生长和死亡。[2]酸性神经酰胺酶活性的抑制使肿瘤细胞抗肿瘤剂辐射的作用敏感。[2]卡莫氟比替莫唑胺更有效,是一种能够杀死成人和儿童胶质母细胞瘤的小分子药物。[3][4]

医疗用途

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卡莫氟的产品营销始于1981年。多年来,卡莫氟在中国日本芬兰也被用作根治性切除的结直肠癌患者的辅助化疗。[5]试验和元分析证实,该药物对这种癌症类型的患者有效,延长了他们的生存期。[6]

卡莫氟已被证明可抑制3C样蛋白酶,因此是一种有前途的先导化合物,可用于开发新的COVID-19抗病毒治疗。[7]

副作用

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与氟尿嘧啶一样,卡莫氟会诱发白质脑病,其特征是大脑中的白质进行性损伤并伴有类似中风的症状。[8][9][10]

一项针对小肝细胞癌的临床试验被提前终止,因为56%的接受治疗的患者有不可接受的副作用。此外,该治疗对1期和2期癌症患者没有生存优势。[11]这可能是为什么卡莫氟从未在美国获得FDA批准的原因。[12]

化学合成

编辑

Ozaki等人报道了通过用光气和己胺处理氟尿嘧啶合成的卡莫氟。[13]Xiong等人。报道了一种合成卡莫氟的替代方法。化学制剂和结构可以在这里找到。[1]

参考文献

编辑
  1. ^ 1.0 1.1 Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF. Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs. Chem Rev. Dec 2016, 116 (23): 14379–14455. PMC 7717319 . PMID 27960273. doi:10.1021/acs.chemrev.6b00209. 
  2. ^ 2.0 2.1 2.2 2.3 Realini, Natalia; Solorzano, Carlos; Pagliuca, Chiara; Pizzirani, Daniela; Armirotti, Andrea; Luciani, Rosaria; Paola Costi, Maria; Bandiera, Tiziano; Piomelli, Daniele. Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity. Scientific Reports. Jan 2013, 3 (1035): 1035. Bibcode:2013NatSR...3E1035R. PMC 3539145 . PMID 23301156. doi:10.1038/srep01035. 
  3. ^ Doan, Ninh B.; Nguyen, Ha S.; Montoure, Andrew; Al-Gizawiy, Mona M.; Mueller, Wade M.; Kurpad, Shekar; Rand, Scott D.; Connelly, Jennifer M.; Chitambar, Christopher R. Acid ceramidase is a novel drug target for pediatric brain tumors. Oncotarget. 2017-03-01, 8 (15): 24753–24761. ISSN 1949-2553. PMC 5421885 . PMID 28445970. doi:10.18632/oncotarget.15800. 
  4. ^ Doan, Ninh B.; Alhajala, Hisham; Al-Gizawiy, Mona M.; Mueller, Wade M.; Rand, Scott D.; Connelly, Jennifer M.; Cochran, Elizabeth J.; Chitambar, Christopher R.; Clark, Paul. Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency. Oncotarget. 2017-11-23, 8 (68): 112662–112674. ISSN 1949-2553. PMC 5762539 . PMID 29348854. doi:10.18632/oncotarget.22637. 
  5. ^ Sakamoto J, Oba K, Matsui T, Kobayashi M. Efficacy of oral anticancer agents for colorectal cancer. Dis. Colon Rectum. Oct 2006, 49 (10 Suppl): S82–91. PMID 17106820. S2CID 30655861. doi:10.1007/s10350-006-0601-7. 
  6. ^ Sakamoto, J; Hamada, C; Rahman, M; Kodaira, S; Ito, K; Nakazato, H; Ohashi, Y; Yasutomi, M. An Individual Patient Data Meta-analysis of Adjuvant Therapy with Carmofur in Patients with Curatively Resected Colon Cancer. Japanese Journal of Clinical Oncology. 2005, 35 (9): 536–544. PMID 16155120. doi:10.1093/jjco/hyi147 . 
  7. ^ Jin, Zhenming; Zhao, Yao; Sun, Yuan; Zhang, Bing; Wang, Haofeng; Wu, Yan; Zhu, Yan; Zhu, Chen; Hu, Tianyu; Du, Xiaoyu; Duan, Yinkai; Yu, Jing; Yang, Xiaobao; Yang, Xiuna; Yang, Kailin; Liu, Xiang; Guddat, Luke W.; Xiao, Gengfu; Zhang, Leike; Yang, Haitao; Rao, Zihe. Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur. Nature Structural and Molecular Biology. Dec 2020, 27 (6): 529–532. PMID 32382072. doi:10.1038/s41594-020-0440-6 . 
  8. ^ Yamada T, Okamura S, Okazaki T, et al. Leukoencephalopathy following treatment with carmofur: a case report and review of the Japanese literature. Asia-Oceania Journal of Obstetrics and Gynaecology. June 1989, 15 (2): 161–8. PMID 2667512. doi:10.1111/j.1447-0756.1989.tb00171.x. 
  9. ^ Mizutani T. [Leukoencephalopathy caused by antineoplastic drugs]. Brain Nerve. February 2008, 60 (2): 137–41. PMID 18306661 (日语). 
  10. ^ Baehring JM, Fulbright RK. Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients. J Neurol Neurosurg Psychiatry. May 2008, 79 (5): 535–9. PMID 17682013. S2CID 38293604. doi:10.1136/jnnp.2007.123737. 
  11. ^ Yamamoto M, Arii S, Sugahara K, Tobe T. Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. Br J Surg. Mar 1996, 83 (3): 336–40. PMID 8665186. S2CID 28134419. doi:10.1002/bjs.1800830313. 
  12. ^ 引用错误:没有为名为Shelton 20162的参考文献提供内容
  13. ^ Ozaki S, Nagase T, Ahmad S, Tamai H, Hoshi A, Iigo M. Synthesis and antitumor activity of 1- or 3-(alpha-hetero substituted)alkyl-5-fluorouracil derivatives. Nucleic Acids Symp Ser. 1987, 18 (18): 1–4. PMID 3697106.