Design, Synthesis of Pentacyclic Triterpenoid Glucose Conjugate and in vitro Activity against Influenza Virus

doi:10.6023/cjoc202111008

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (5): 1453-1462.DOI: 10.6023/cjoc202111008 Previous Articles Next Articles

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五环三萜葡萄糖缀合物的设计、合成及体外抗流感病毒活性研究

蔡铭^a, 邵亮^a, 杨帆^a, 张继虹^a, 俞飞^a^,^b^,^*()

a 昆明理工大学医学院昆明 650500
b 北京大学药学院天然药物及仿生药物国家重点实验室北京 100191

收稿日期:2021-11-03 修回日期:2021-12-31 发布日期:2022-01-27
通讯作者: 俞飞
基金资助:
国家自然科学基金(22167018); 天然药物及仿生药物国家重点实验室开放基金(K202003); 云南省科技厅科技计划(2019FB125); 云南省科技厅科技计划(2018FB145)

Design, Synthesis of Pentacyclic Triterpenoid Glucose Conjugate and in vitro Activity against Influenza Virus

Ming Cai^a, Liang Shao^a, Fan Yang^a, Jihong Zhang^a, Fei Yu^a^,^b()

a Medical Faculty, Kunming University of Science and Technology, Kunming 650500
b State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191

Received:2021-11-03 Revised:2021-12-31 Published:2022-01-27
Contact: Fei Yu
Supported by:
National Natural Science Foundation of China(22167018); Foundation of State Key Laboratory of Natural and Biomimetic Drugs(K202003); Yunnan Fundamental Research Projects(2019FB125); Yunnan Fundamental Research Projects(2018FB145)

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Abstract

Previous studies have revealed that oleanolic acid (OA) C28-glucose conjugate displayed potent anti-influenza viral activity in vitro. However, the effect of pentacyclic triterpene scaffold coupled with glucose on anti-influenza virus activity has not been clarified. Herein, as a continuous further study, a series of pentacyclic triterpene-glucose conjugates were prepared via CuAAC reaction, and the anti-influenza activity of these compounds was evaluated in vitro. Among them, compound 4d, an betulinic acid (BA)-glucose conjugate, showed potent anti-influenza virus activity (IC₅₀ value of 9.09 μmol/L), and no obvious cytotoxic effect on MDCK (Madin-Darbey Canine Kidney) cells was observed (CC₅₀>100 μmol/L). Structure-activity relationship studies showed that both triterpene scaffolds and glucose moiety have important effects on the anti-viral activity. Overall, this finding further extends the utility of triterpene derivatives in anti-influenza virus drug design.

Key words: pentacyclic triterpene, influenza virus, entry inhibitors, structure-activity relationship

Cite this article

Ming Cai, Liang Shao, Fan Yang, Jihong Zhang, Fei Yu. Design, Synthesis of Pentacyclic Triterpenoid Glucose Conjugate and in vitro Activity against Influenza Virus[J]. Chinese Journal of Organic Chemistry, 2022, 42(5): 1453-1462.

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Fig. & Tab. 7

References 18

[1]	Li, H.; Li, M.; Xu, R.; Wang, S.; Zhang, Y.; Zhang, L.; Zhou, D.; Xiao, S. Eur. J. Med. Chem. 2019, 163, 560. doi: 10.1016/j.ejmech.2018.12.006
[2]	Chintakrindi, A. S.; Gohil, D. J.; Chowdhary, A. S.; Kanyalkar, M. A. Bioorg. Med. Chem. 2020, 28, 115191. doi: 10.1016/j.bmc.2019.115191
[3]	Cline, T. D.; Karlsson, E. A.; Seufzer, B. J.; Schultz-Cherry, S. J. Virol. 2013, 87, 1411. doi: 10.1128/JVI.02682-12 pmid: 23152519
[4]	Chintakrindi, A. S.; Gohil, D. J.; Kothari, S. T.; Chowdhary, A. S.; Kanyalkar, M. A. Med. Chem. Res. 2018, 27, 1013. doi: 10.1007/s00044-017-2124-2
[5]	Naesens, L.; Stevaert, A.; Vanderlinden, E. Curr. Opin. Pharmacol. 2016, 30, 106. doi: S1471-4892(16)30088-1 pmid: 27570127
[6]	Lee, N.; Hurt, A. C. Curr. Opin. Infect. Dis. 2018, 31, 520. doi: 10.1097/QCO.0000000000000498
[7]	Yen, H. L.; Hoffmann, E.; Taylor, G.; Scholtissek, C.; Monto, A. S.; Webster, R. G.; Govorkova, E. A. J. Virol. 2006, 80, 8787. doi: 10.1128/JVI.00477-06
[8]	Tian, Z.; Si, L.; Meng, K.; Meng, K.; Zhou, X.; Zhang, Y.; Zhou, D.; Xiao, S. Eur. J. Med. Chem. 2017, 134, 133. doi: 10.1016/j.ejmech.2017.03.087
[9]	Yu, M.; Si, L.; Wang, Y.; Wu, Y.; Yu, F.; Jiao, P.; Shi, Y.; Wang, H.; Xiao, S.; Fu, G.; Tian, K.; Wang, Y.; Guo, Z.; Ye, X.; Zhang, L.; Zhou, D. J. Med. Chem. 2014, 57, 10058. doi: 10.1021/jm5014067
[10]	Luo, M.; Wu, X.; Li, Y.; Guo, F. Molecules 2021, 26, 895. doi: 10.3390/molecules26040895
[11]	Su, Y.; Meng, L.; Sun, J.; Li, W.; Shao, L.; Chen, K.; Zhou, D., Yang, F.; Yu, F. Eur. J. Med. Chem. 2019, 182, 111622. doi: 10.1016/j.ejmech.2019.111622
[12]	Shao, L.; Yang, F.; Li, W. J.; Yu, F. Chin. J. Org. Chem. 2021, 41, 2454. (in Chinese) doi: 10.6023/cjoc202010029
	(邵亮, 杨帆, 李维嘉, 俞飞, 有机化学, 2021, 41, 2454.)
[13]	Nouri-Felekori, M.; Nezafati, N.; Moraveji, M.; Hesaraki, S.; Ramezani, T. Int. J. Biol. Macromol. 2021, 183, 2030. doi: 10.1016/j.ijbiomac.2021.06.005 pmid: 34097959
[14]	Agrahari, A. K.; Bose, P.; Jaiswal, M. K.; Rajkhowa, S.; Singh, A. S.; Hotha, S.; Mishra, N.; Tiwari, V. K. Chem. Rev. 2021, 121, 7638. doi: 10.1021/acs.chemrev.0c00920 pmid: 34165284
[15]	Devaraj, N. K.; Finn, M. G. Chem. Rev. 2021, 121, 6697. doi: 10.1021/acs.chemrev.1c00469 pmid: 34157843
[16]	Chen, D.; Zhang, P.; Sun, Y.; Wang, P.; Zhang, C.; Kong, L.; Zhang, J.; Sun, H.; Wen, X. Org. Biomol. Chem. 2016, 14, 11154. doi: 10.1039/C6OB02126C
[17]	Li, H.; Li, M.; Xu, R.; Wang, S.; Zhang, Y.; Zhang, L.; Zhou, D.; Xiao, S. Eur. J. Med. Chem. 2019, 163, 560. doi: 10.1016/j.ejmech.2018.12.006
[18]	Spackman, E.; Sitaras, I. Methods. Mol. Biol. 2020, 2123, 11. doi: 10.1007/978-1-0716-0346-8_2 pmid: 32170677

化合物结构式	化合物		细胞存活率/%		流感病毒抑制率/%
	4		106.12±8.38		59.00±10.18
	4c		91.27±0.03		8.46±23.27
	4d		106.53±9.50		92.94±1.45
	5		4.08±0.34		99.48±1.08
	5c		110.24±0.002		NT
	5d		105.15±11.41		54.16±11.54
	6		3.98±1.90		95.14±7.36
	6c		56.04±0.008		58.51±4.72
	6d		74.02±6.92		80.65±16.47
化合物结构式		化合物		细胞存活率/%		流感病毒抑制率/%
		7		3.30±0.06		99.85±0.31
		7c		103.68±0.02		10.43±5.20
		7d		4.18±1.45		97.41±3.72
		8		102.05±10.33		70.99±14.04
		8c		73.23±3.62		96.62±15.17
		8d		101.63±6.89		91.68±8.14

化合物结构式	化合物		细胞存活率/%		流感病毒抑制率/%
	4		106.12±8.38		59.00±10.18
	4c		91.27±0.03		8.46±23.27
	4d		106.53±9.50		92.94±1.45
	5		4.08±0.34		99.48±1.08
	5c		110.24±0.002		NT
	5d		105.15±11.41		54.16±11.54
	6		3.98±1.90		95.14±7.36
	6c		56.04±0.008		58.51±4.72
	6d		74.02±6.92		80.65±16.47
化合物结构式		化合物		细胞存活率/%		流感病毒抑制率/%
		7		3.30±0.06		99.85±0.31
		7c		103.68±0.02		10.43±5.20
		7d		4.18±1.45		97.41±3.72
		8		102.05±10.33		70.99±14.04
		8c		73.23±3.62		96.62±15.17
		8d		101.63±6.89		91.68±8.14

Compound	CC₅₀^a/(μmol•L^–1)	IC₅₀^b/(μmol•L^–1)	SI^c
OSV-p^d	>100	1.82	>54.59
2^d	>100	5.47	>18.28
4d	>100	9.09	>10.99
8d	>100	12.56	>7.96

Compound	CC₅₀^a/(μmol•L^–1)	IC₅₀^b/(μmol•L^–1)	SI^c
OSV-p^d	>100	1.82	>54.59
2^d	>100	5.47	>18.28
4d	>100	9.09	>10.99
8d	>100	12.56	>7.96

Compd.	Binding energy^a/(kJ•mol^–1)	Chemical feature^b
4c	–22.01	CHB^c, π-Alkyl
5c	–14.69	CHB, π-DHB^d, Alkyl
6c	–22.30	CHB, Alkyl
7c	–21.46	CHB, π-DHB, π-Alkyl
8c	–21.42	CHB, π-Sigma, π-Alkyl
4d	–24.98	CHB, π-Cation, π-Alkyl
5d	–21.55	CHB, π-Anion, π-Alkyl
6d	–22.93	CHB, π-Cation, π-Alkyl
7d	–22.55	CHB, π-Alkyl
8d	–23.10	CHB, π-Anion, Alkyl

五环三萜葡萄糖缀合物的设计、合成及体外抗流感病毒活性研究

Design, Synthesis of Pentacyclic Triterpenoid Glucose Conjugate and in vitro Activity against Influenza Virus

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