利巴韦林的结构修饰及应用研究进展

doi:10.6023/cjoc202601025

摘要/Abstract

对核苷类似物进行结构修饰是研发新型药物的重要策略. 利巴韦林作为代表性核苷类似物之一, 是一种广谱抗病毒药物. 然而, 长期或过量使用可能导致白细胞减少、抑制红细胞生成等副作用. 因此, 诸多科研工作者致力于开发高效低毒的利巴韦林衍生物. 系统总结了利巴韦林的结构修饰及应用, 主要包括糖基修饰和碱基修饰. 同时, 也探讨了新的合成方法及其在药物开发中的潜在应用, 以期为新型抗病毒药物的研发提供参考.

关键词: 利巴韦林, 结构修饰, 应用, 糖基修饰, 碱基修饰

Structural modification of nucleoside analogues is an important strategy for developing novel drugs. Ribavirin, as one of the representative nucleoside analogues, is a broad-spectrum antiviral nucleoside drug. However, its prolonged or excessive use can lead to side effects, such as reduction in white blood cell count and inhibition of red blood cell production. Therefore, extensive research has focused on developing ribavirin derivatives with improved efficacy and reduced toxicity. This review systematically summarizes the structural modifications and applications of ribavirin, primarily including glycosyl modifications and base modifications. Additionally, novel synthetic methods and potential applications in drug development are discussed, providing insights for the development of novel antiviral drugs.

Key words: Ribavirin, structural modification, application, glycosyl modification, base modification

引用此文

吕洁, 李停停. 利巴韦林的结构修饰及应用研究进展[J]. 有机化学, 2026, 46(8): 3012-3024.

Jie Lv, Tingting Li. Recent Advances in the Structural Modifications and Applications of Ribavirin[J]. Chinese Journal of Organic Chemistry, 2026, 46(8): 3012-3024.

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图/表 27

Figure 1. Significance of nucleoside modification and structural modification of ribavirin

Figure 2. Glycosyl modification of ribavirin

Figure 3. Synthesis of 5-O-β-D-glucopyranosyl derivatives of ribavirin

Figure 4. CAL-B catalyzed 5-OH selective acylation reaction of ribavirin

Figure 5. 3-Step synthesis of 5-O-substituted ribavirin deri- vatives

Figure 6. CAL-B catalyzed one-step synthesis of 5-O-acylated ribavirin derivatives

Figure 7. CAL-B catalyzed synthesis of high yield 5-O-acylated vinyl ester

Figure 8. Synthesis and biological activity of hemoglobin-riba- virin conjugate

Figure 9. Synthesis of drug derivatives catalyzed by CAL-B

Figure 10. Synthesis of 5-O-phosphoramidates of ribavirin

Figure 11. Synthesis of 5-O-phosphoramidate ribavirin deri- vatives

Figure 12. Enzymatic synthesis of 5-O-acylated ribavirin esters by transesterification

Figure 13. Synthesis of L-amino acid ester prodrugs of ribavirin

Figure 14. Synthesis of macromolecular prodrugs of ribavirin

Figure 15. Synthesis of ribavirin-L-Val-glycochenodeoxy-cholic acid (GCDCA)

Figure 16. NHC/Boric acid catalysis for the synthesis of 5-O- acylated ribavirin derivatives

Figure 17. NHC catalysis for the synthesis of 3-O-acylated ribavirin derivatives

Figure 18. Modification of the 2-OH group of ribavirin

Figure 19. Synthesis of the 2-OH group modified ribavirin derivative

Figure 20. Synthesis of 2,3-O-acylated ribavirin derivatives

Figure 21. Synthesis of 2,3,5-O-modified ribavirin derivatives

Figure 22. Base modification of ribavirin

Figure 23. Synthesis of imine-modified ribavirin derivatives

Figure 24. Synthesis of azide-modified ribavirin derivatives

Figure 25. Synthesis of 5-aryltriazole ribonucleosides

Figure 26. Synthesis of alkyne-modified ribavirin derivatives

Figure 27. Synthesis of hydrazide-modified ribavirin derivatives

参考文献 58

[1]	Saenger, W. Angew. Chem. Int. Ed. 1973, 12, 591.
[2]	Leonard, N. J.; Tolman, G. L. Ann. N. Y. Acad. Sci. 1975, 255, 43.
[3]	Banoub, J. H.; Newton, R. P.; Esmans, E.; Ewing, D. F.; Mackenzie, G. Chem. Rev. 2005, 105, 1869.
[4]	Peters, G. M.; Davis, J. T. Chem. Soc. Rev. 2016, 45, 3188.
[5]	Roy, B.; Depaix, A.; Perigaud, C.; Peyrottes, S. Chem. Rev. 2016, 116, 7854.
[6]	Dimakos, V.; Taylor, M. S. Chem. Rev. 2018, 118, 11457.
[7]	Pu, F.; Ren, J.; Qu, X. Chem. Soc. Rev. 2018, 47, 1285.
[8]	Fialho, D. M.; Roche, T. P.; Hud, N. V. Chem. Rev. 2020, 120, 4806.
[9]	Shet, H.; Sahu, R.; Sanghvi, Y. S.; Kapdi, A. R. Chem. Rec. 2022, 22, e202200066.
[10]	Seley-Radtke, K. L.; Yates, M. K. Antiviral Res. 2018, 154, 66.
[11]	Yates, M. K.; Seley-Radtke, K. L. Antiviral Res. 2019, 162, 5.
[12]	Hu, H.; Mady Traore, M. D.; Li, R.; Yuan, H.; He, M.; Wen, B.; Gao, W.; Jonsson, C. B.; Fitzpatrick, E. A.; Sun, D. J. Med. Chem. 2022, 65, 12044.
[13]	Thomson, P. J.; Illing, P. T.; Farrell, J.; Alhaidari, M.; Bell, C. C.; Berry, N.; O’Neill, P. M.; Purcell, A. W.; Park, K. B.; Naisbitt, D. J. Allergy 2020, 75, 636.
[14]	Lin, X.; Liang, C.; Zou, L.; Yin, Y.; Wang, J.; Chen, D.; Lan, W. Eur. J. Med. Chem. 2021, 214, 113233.
[15]	Knight, V.; Wilson, S.; Quarles, J.; Greggs, S.; McClung, H.; Waters, B.; Cameron, R.; Zerwas, J.; Couch, R. Lancet 1981, 318, 945.
[16]	Reichard, O.; Andersson, J.; Schvarcz, R.; Weiland, O. Lancet 1991, 337, 1058.
[17]	Wiley, J. S.; Jones, S. P.; Sawyer, W. H.; Paterson, A. R. J. Clin. Invest. 1982, 69, 479.
[18]	Bonkovsky, H. L.; Stefancyk, D.; McNeal, K.; Banner, B. F.; Liu, Q.; Zucker, G. M.; Israel, J.; Stagias, J.; Colker, J. Digest. Dis. Sci. 2001, 46, 2051.
[19]	Santagostino, E.; Rumi, M. G.; Rivi, M.; Colombo, M.; Mannucci, P. M. Blood 2002, 99, 1089.
[20]	Hunsucker, S. A.; Mitchell, B. S.; Spychala, J. Pharmacol. Ther. 2005, 107, 1.
[21]	Smal, C.; Vertommen, D.; Bertrand, L.; Ntamashimikiro, S.; Rider, M. H.; Van Den Neste, E.; Bontemps, F. J. Biol. Chem. 2006, 281, 4887.
[22]	Li, F.; Maag, H.; Alfredson, T. J. Pharm. Sci. 2008, 97, 1109.
[23]	Saiki, Y.; Yoshino, Y.; Fujimura, H.; Manabe, T.; Kudo, Y.; Shimada, M.; Mano, N.; Nakano, T.; Lee, Y.; Shimizu, S.; Oba, S.; Fujiwara, S.; Shimizu, H.; Chen, N.; Nezhad, Z. K.; Jin, G.; Fukushige, S.; Sunamura, M.; Ishida, M.; Motoi, F.; Egawa, S.; Unno, M.; Horii, A. Biochem. Biophys. Res. Commun. 2012, 421, 98.
[24]	Thornton, P. J.; Kadri, H.; Miccoli, A.; Mehellou, Y. J. Med. Chem. 2016, 59, 10400.
[25]	Pawlotsky, J. M.; Dahari, H.; Neumann, A. U.; Hezode, C.; Germanidis, G.; Lonjon, I.; Castera, L.; Dhumeaux, D. Gastroenterology 2004, 126, 703.
[26]	Swenson, C. S.; Velusamy, A.; Argueta-Gonzalez, H. S.; Heemstra, J. M. J. Am. Chem. Soc. 2019, 141, 19038.
[27]	Muralidharan, A.; Boukany, P. E. Trends Biotechnol. 2023, 42, 780.
[28]	Mehellou, Y.; Rattan, H. S.; Balzarini, J. J. Med. Chem. 2018, 61, 2211.
[29]	Sun, Y.; Kang, D.; Gao, S. Chin. J. Med. Chem. 2021, 31, 55 (in Chinese).
	(孙彦莹, 康东伟, 高升华, 中国药物化学杂志, 2021, 31, 55.)
[30]	Hanna, N. B.; Robins, R. K.; Revankar, G. R. Carbohydr. Res. 1987, 165, 267.
[31]	Tamarez, M.; Morgan, B.; Wong, G. S. K.; Tong, W.; Bennett, F.; Lovey, R.; McCormick, J. L.; Zaks, A. Org. Process Res. Dev. 2002, 7, 951.
[32]	Li, Q.; Chen, S.; Jiang, N. Chin. J. Org. Chem. 2004, 24, 1432 (in Chinese).
	(李清寒, 陈淑华, 蒋宁, 有机化学, 2004, 24, 1432.)
[33]	Li, Z.; Chen, S.; Jiang, N.; Cui, G. Nucleosides, Nucleotides Nucleic Acids 2003, 22, 419.
[34]	Liu, B. K.; Wang, N.; Wu, Q.; Xie, C. Y.; Lin, X. F. Biotechnol. Lett. 2005, 27, 717.
[35]	Liu, B. K.; Wang, N.; Chen, Z. C.; Wu, Q.; Lin, X. F. Bioorg. Med. Chem. Lett. 2006, 16, 3769.
[36]	Liu, B. K.; Wu, Q.; Xu, J. M.; Lin, X. F. Chem. Commun. 2007, 295.
[37]	Brookes, S.; Biessels, P.; Ng, N. F. L.; Woods, C.; Bell, D. N.; Adamson, G. Bioconjugate Chem. 2006, 17, 530.
[38]	Li, X.; Wu, Q.; Lu, M.; Zhang, F.; Lin, X. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 2734.
[39]	Liu, B.; Qian, X.; Wu, Q.; Lin, X. Enzyme Microb. Technol. 2008, 43, 375.
[40]	Li, X.; Wu, Q.; Chen, Z.; Gong, X.; Lin, X. Polymer 2008, 49, 4769.
[41]	Leisvuori, A.; Aiba, Y.; Lonnberg, T.; Poijarvi-Virta, P.; Blatt, L.; Beigelman, L.; Lonnberg, H. Org. Biomol. Chem. 2010, 8, 2131.
[42]	Oleynikova, I. A.; Kulak, T. I.; Bolibrukh, D. A.; Kalinichenko, E. N. Helv. Chim. Acta 2013, 96, 463.
[43]	Ni, Z.; Lin, X. J. Mol. Model. 2013, 19, 349.
[44]	Xu, F.; Zhang, M.; Wu, Q.; Lin, X. J. Mol. Catal. B: Enzym. 2014, 105, 49.
[45]	Kryger, M. B. L.; Wohl, B. M.; Smith, A. A. A.; Zelikin, A. N. Chem. Commun. 2013, 49, 2643.
[46]	Dong, Z.; Li, Q.; Guo, D.; Shu, Y.; Polli, J. E. J. Pharm. Sci. 2015, 104, 2864.
[47]	Riber, C. F.; Hinton, T. M.; Gajda, P.; Zuwala, K.; Tolstrup, M.; Stewart, C.; Zelikin, A. N. Mol. Pharm. 2017, 14, 234.
[48]	Lv, J.; Zou, J.; Nong, Y.; Song, J.; Shen, T.; Cai, H.; Mou, C.; Lyu, W.; Jin, Z.; Chi, Y. R. ACS Catal. 2023, 13, 9567.
[49]	Ramasamy, K. S.; Tam, R. C.; Bard, J.; Averett, D. R. J. Med. Chem. 2000, 43, 1019.
[50]	Vivet-Boudou, V.; Paillart, J. C.; Burger, A.; Marquet, R. Nucleosides, Nucleotides Nucleic Acids 2007, 26, 743.
[51]	Xu, R. G.; Liu, F.; Liu, Y. J.; Chen, B. Q.; Liu, F. W. Chin. J. Chem. 2013, 31, 855.
[52]	Qureshi, A.; Bano, S. Med. Chem. Res. 2024, 33, 1554.
[53]	Wang, Q.; Hu, W.; Wang, S.; Pan, Z.; Tao, L.; Guo, X.; Qian, K.; Chen, C.-H.; Lee, K.-H.; Chang, J. Eur. J. Med. Chem. 2011, 46, 4178.
[54]	Kini, G. D.; Robins, R. K.; Avery, T. L. J. Med. Chem. 2002, 32, 1447.
[55]	Wu, Q.; Qu, F.; Wan, J.; Zhu, X.; Xia, Y.; Peng, L. Helv. Chim. Acta 2004, 87, 811.
[56]	Wan, J. Q.; Zhu, R. Z.; Xia, Y.; Qu, F. Q.; Wu, Q. Y.; Yang, G. F.; Neyts, J.; Peng, L. Tetrahedron Lett. 2006, 47, 6727.
[57]	Chung, D. H.; Kumarapperuma, S. C.; Sun, Y.; Li, Q.; Chu, Y. K.; Arterburn, J. B.; Parker, W. B.; Smith, J.; Spik, K.; Ramanathan, H. N.; Schmaljohn, C. S.; Jonsson, C. B. Antiviral Res. 2008, 79, 19.
[58]	Zhang, Y.; Wang, L.; Peng, Y.; Lin, D. Chin. J. Synth. Chem. 2010, 18, 712 (in Chinese).
	(张逸伟, 王琳, 彭云铁, 林东恩, 合成化学, 2010, 18, 712.)