主客体络合驱动的开环葫芦脲对琥珀胆碱神经肌肉阻滞的快速拮抗

doi:10.6023/cjoc202601042

摘要/Abstract

设计合成了七个新的开环葫芦脲化合物, 用于研究其通过主客体结合拮抗琥珀胆碱肌肉松弛活性的功能。研究发现化合物ACB-p2具有高水溶性和生物相容性,对小鼠的最大耐受剂量高达1500毫克/千克。化合物ACB-p2对临床唯一的短效神经肌肉阻滞剂琥珀胆碱（SCH）具有高结合亲和力（结合常数K_a = 1.7 × 10⁵ M^-1）。¹H核磁共振实验和密度泛函理论计算研究表明,ACB-p2主要通过其疏水空腔包结琥珀胆碱的胆碱片段实现高效结合,并进一步通过多重分子间C-H•••O-氢键作用稳定。大鼠试验模型揭示, 80 和160 mg/kg剂量的ACB-p2可快速拮抗琥珀胆碱引发的神经肌肉阻滞作用,能将大鼠自主呼吸恢复时间从平均195秒显著缩短至38和23秒,分别对应于11.8和5.9倍的治疗指数, 显示出开环葫芦脲快速拮抗琥珀胆碱的潜力。

关键词: 主客体化学, 开环葫芦脲, 琥珀胆碱, 解药, 神经肌肉阻滞, 超分子拮抗, 药物设计

Seven new acyclic cucurbit[n]urils have been prepared. One of the compounds (ACB-p2) displays high water-solubility and high biocompatibility, with maximum tolerated dose reaching 1500 mg/kg for mice. The compound is revealed to have high binding affinity (K_a = 1.7 × 10⁵ M^-1) in water for succinylcholine (SCH), clinically used short-duration neuromuscular blocking agent. ¹H NMR and density functional theory calculation show that ACB-p2 binds to SCH mainly by encapsulating the choline segment of SCH in its hydrophobic cavity, which is stabilized by multiple intermolecular C-H۰۰۰O hydrogen bonds. The high binding affinity of ACB-p2 for SCH leads to rapid antagonism of the neuromuscular blockade of SCH. For rats, compound ACB-p2 of the 80 and 160 mg/kg doses is capable of shortening the recovery time for spontaneous respiration averagely from 195 seconds to 38 and 23 seconds, respectively, corresponding to therapeutic an index of 11.8 and 5.9.

Key words: host-guest chemistry, acyclic cucurbit[n]uril, succinylcholine, antidote, neuromuscular blockade, supramolecular antagonism, drug design

引用此文

张丹维, 高睿, 冯科, 余尚博, 王辉, 周伟, 黎占亭. 主客体络合驱动的开环葫芦脲对琥珀胆碱神经肌肉阻滞的快速拮抗[J]. 有机化学, doi: 10.6023/cjoc202601042.

Dan-Wei Zhang, Rui Gao, Ke Feng, Shang-Bo Yu, Hui Wang, Wei Zhou, Zhan-Ting Li. Acyclic Cucurbit[n]uril as Supramolecular Antagonist for Rapidly Reversing the Neuromuscular Blockade of Succinylcholine through Host-Guest Complexation[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202601042.

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参考文献

[1] Fu G.; Xu L.; Chen H.; Lin J. BMC Surg.2025, 25, 32.
[2] Raghavendra, T. J. R. Soc. Med.2002, 95, 363.
[3] (a) Orebaugh, S. L. Am. J. Emerg. Med.1999, 17, 715.
(b) Bakhsh, A. Acad. Emerg. Med. 2020, 27, 66.
[4] Nguyen J. Q.; Paetznick C.; Donnelly R. S. Pharmacotherapy2025, 45, 600.
[5] Zhang X.; Cheng Q.; Li L.; Shangguan L.; Li C.; Li S.; Huang F.; Zhang J.; Wang R. Theranostics2019, 9, 3107.
[6] Li M.; Cheng Y.; Fei R.; Xia D.; Zhang Z.; Qi S.; Du J. Chem. Commun.2025, 61, 5982.
[7] Brockett A. T.; Xue W.; King D.; Deng C.-L.; Zhai C.; Shuster M.; Rastogi S.; Briken V.; Roesch M. R.; Isaacs L. Chem2023, 9, 881.
[8] Liu Y.-Y.; Yu X.-Y.; Pan Y.-C.; Yin H.; Chao S.; Li Y.; Ma H.; Zuo M.; Teng K.-X.; Hou J.-L.; Chen Y.; Guo D.-S.; Wang R.; Pei Y.; Pei Z.; Xu J.-F.; Hu X.-Y.; Li C.; Yang Q.-Z.; Wang L.; Liu Y.; Li, Z.-T. Sci. China Chem.2024, 67, 1397.
[9] (a) Liu, C.; Jin, Y.; Li, J.; Wang, Z.; Wang, J.; Tian, W.Chin. J. Chem. 2025, 43, 2053.
(b) Guo Y.; Zhang M.; Gong Z.; Zhao Y.; Shi K.; He L. Design and Biological Application of Macrocyclic Host Molecules-based Nucleic Acid Probes. Acta Chim. Sinica2025, 83, 309-318 (in Chinese)
(郭煜静, 张梦盼, 巩子彤, 赵云莉, 石康琦, 何磊良. 化学学报2025, 83, 309)
(c) Zhang, W.; Su, S.; Yang, P.Chin. J. Org. Chem. 2025, 45, 1395-1401 (in Chinese)
(张文博, 苏思铭, 杨鹏. 有机化学2025, 45, 1395).
(d) Huang S.; Yang, L. ; Wang, L.; Yao H.2025, 45, 3624 (in Chinese)
(黄胜兰, 杨留攀, 王力立, 姚欢. 有机化学2025, 45, 3624)
[10] (a) Zhang X.; Yang X.; Wang Y.; Xu Z.; Yi S.; Guo T.; Liao Y.; Tang X.; Zhang J.; Wang, R. Chin. Chem. Lett.2025, 36, 109854.
(b) Liu J.; Yin F.; Ren Y.; Ming M.; Xie H.; Cai X.; Li J.-J.; Guo D.-S.; Wang, K.-R. J. Med. Chem.2025, 68, 24456.
[11] Yue Y.-X.; Lin Y.-L.; Chen M.-M.; Tian H.-W.; Ma R.; Wang Z.-H.; Chen F.-Y.; Pan Y.-C.; Guo, D.-S. Sci. China Chem.2024, 67, 1697.
[12] Liu Z.; Chen H.; Guo L.; Sun X.; Zhang Z.-Y.; Chen J.; Dong M.; Li, C. Chin. Chem. Lett.2024, 35, 109666.
[13] (a) Yang F.; Wang G.; Huang K.; Xu Y.; Feng X.; Wang W.; Wei, W. Sci. China Chem.2025, 68, 1009.
(b) He M.; Ma Z.; Zhang Z.; Zhang L.; Zhang S.; Wang R.; Leng X.; Li Y.; Fan J.; Sun W.; Peng, X. Sci. China Chem.2024, 67, 3875.
(c) Han X.-W.; Zhang G.-L.; Chen P.; Zhang J.; Shan G.; Qi C.; Tang B. Z.; Feng, H.-T. Sci. China Chem.2025, 68, 1550.
(d) Lei Z.; Song Y.-H.; Leng Y.-L.; Gu Y.-J.; Yu M.; Chen Y.; Yu Q.; Liu, Y. J. Med. Chem.2025, 68, 5891.
[14] (a) Wang, K.; Guo, D.-S.; Zhang, H.-Q.; Li, D.; Zheng, X.-L.; Liu, Y.J. Med. Chem. 2009, 52, 6402.
(b) Lin Q.; Xing J.; Liu Y.-Y.; Wu G.; Liu S.-J.; Wang H.; Zhou W.; Li Z.-T.; Zhang, D.-W. Chin. Chem. Lett.2024, 35, 109119.
(c) Chen F.-Y.; Geng W.-C.; Cai K.; Guo, D.-S. Chin. Chem. Lett.2024, 35, 109161.
(d) Yin H.; Zhang X.; Wei J.; Lu S.; Bardelang D.; Wang R. Theranostics2021, 11, 1513.
(e) Deng C.-L.; Murkli S. L.; Isaacs, L. D. Chem. Soc. Rev.2020, 49, 7516.
[15] (a) Gao J.-M.; Li W.-B.; Yi Y.; Wei J.-J.; Gong M.-X.; Pan B.-B.; Su X.-C.; Pan Y.-C.; Guo D.-S.; Gong Q.-H. Biomaterials2025, 322, 123378.
(b) Chen M.-M.; Tian H.-W.; Cheng Y.-Q.; Yue Y.-X.; Pan Y.-C.; Guo, D.-S. Adv. Healthc. Mater.2025, 14, 2402732.
(c) Fang Z.; Zhang Z.; Wang R.; Li S.; Lin S.; Zhou Y.; Chen J.; Li C.; Meng, Q. J. Med. Chem.2024, 67, 21568.
[16] Ma Y.-L.; Yan S.; Xu X.-J.; Cao H.; Wang, R. Chin. Chem. Lett.2024, 35, 108645.
[17] (a) Xing J.; Li Y.-S.; Lin Q.; Liu Y.-Y.; Li Q.; Qi Q.-Y.; Wang H.; Zhao G.; Zhang J.; Zhang D.-W.; Zhou W.; Li, Z.-T. Chin. J. Chem.2025, 43, 1021.
(b) Liu P.-P.; Xing J.-B.; Liu Y.-Y.; Feng K.; Wang H.; Zhang D.-W.; Zhou W.; Zhao G.; Zhang J.; Li, Z.-T. Chin. Chem. Lett.2025, 36, 110831.
[18] (a) Su Q.-L.; Chen J.-F.; Sun X.-M.; Liu J.; Dai X.-Y.; Wei T.-B.; Yao H.; Lin, Q. Chin. J. Chem.2024, 42, 2471.
(b) Wang P.; Li Y.; Zhao L.; Yang Y.; Kang X.; Yang T.; Cao F.; Cheng L.; Cao, L. Chin. J. Chem.2025, 43, 1173.
(c) Yan K.; Shi Y.; Wang Z.; Jiao J.; Wang K.; Hu, X.-Y. Chin. J. Chem.2025, 43, 1651.
(d) Xu C.-Y.; Luan X.-L.; Cui Y.-Y.; Yang, C.-X. Chin. Chem. Lett.2025, 36, 110937.
(e) Wu, S.; Feng, K.; Niu, J.; Xu, J.; Mo, H.; She, X.; Yu, S.-B.; Li, Z.-T.; Yan, S.Toxins 2025, 17, 104.
(f) Zhang, C.; Ren, J.; Ouyang, G.; Liu, M.Chin. J. Org. Chem. 2025, 45, 4171-4177 (in Chinese)
(赵晨阳, 任静晓, 欧阳光辉, 刘鸣华. 有机化学2025, 45, 4171).
[19] (a) Keating, G. M. Drugs2016, 76, 1041.
(b) Zhao, C.-D.; Cai, W.; Chen, W.-J.; Yao, H.; Wang, S.-M.; Li, K.; Ma, Y.-L.; Wang, L.-L.; Yang, L.-P.Theranostics 2024, 14, 5219.
(c) Yin Y.; Wang H.; Wu J.; Wang, L. Yang L.; Zhao C.; Yao, H. Chin. J. Org. Chem.2025, 45, 2953 (in Chinese)
(尹烨, 王惠, 吴建芳, 王力立, 杨留攀, 赵承达, 姚欢. 有机化学2025, 45, 2953).
[20] (a) Wu, Y.; Liu, E.; Shi, C.; Stoddart, J. F.CCS Chem. 2025, 7, 1935.
(b) Li H.; Yang X.; Sun, M. Chin. Chem. Lett.2025, 36, 110651.
(c) Liu Z.; Liu, Y. Chem. Soc. Rev.2022, 51, 4786.
(d) Liu Z.; Lin W.; Liu, Y. Acc. Chem. Res.2022, 55, 3417.
[21] Li Z.-T.; Yu S.-B.; Liu Y.; Tian J.; Zhang, D.-W. Acc. Chem. Res.2022, 55, 2316.
[22] (a) Yuan X.; Xu D.-F.; Song Y.; Zhang Y.-M.; Liu, Y. ACS Appl. Polym. Mater.2024, 6, 4331.
(b) Park, K. M.; Suh, K.; Jung, H.; Lee, D.-W.; Ahn, Y.; Kim, J.; Baek, K.; Kim, K.Chem. Commun. 2009, 71.
(c) Oun R.; Floriano R. S.; Isaacs L.; Rowan E. G.; Wheate, N. J. Toxicol. Res.2014, 3, 447.
(d) Zhu Y.-J.; Lv Z.-M.; Zhu H.-F.; Qi Q.-Y.; Yu S.-B.; Tian J.; Zhou W.; Li, Z.-T. Chin. Chem. Lett.2026, 37, 111353.
(e) Mao L.; Li S.; Zhang X.; Li Z.-T.; Ma, D. Chin. Chem. Lett.2024, 35, 109363.
[23] (a) Liu H.-K.; Lin F.; Yu S.-B.; Wu Y.; Lu S.; Liu Y.-Y.; Qi Q.-Y.; Cao J.; Zhou W.; Li X.; Wang H.; Zhang D.-W.; Li Z.-T.; Ma, D. J. Med. Chem.2022, 65, 16893.
(b) Li M.; Zhang M.; Fei R.; Zhang Y.; Xia D.; Qi S.; Du, J. Precis. Med. Engin.2025, 2, 100034.
[24] Ma D.; Hettiarachchi G.; Nguyen D.; Zhang B.; Wittenberg J. B.; Zavalij P. Y.; Briken V.; Isaacs L. Nat. Chem.2012, 4, 503.
[25] Ma D.; Zhang B.; Hoffmann U.; Sundrup M. G.; Eikermann M.; Isaacs, L. Angew. Chem. Int. Ed.2012, 51, 11358.
[26] Feng K.; Liu Y.-Y.; Zong Y.; Lei Z.; Wu Y.; Yang J.; Lin F.; Qi Q.-Y.; Li Q.; Zhuang S.-Y.; Zhang J.; Tian J.; Zhou W.; Ma D.; Zhang D.-W.; Li Z.-T.; Yu, S.-B. J. Med. Chem.2024, 67, 17905.
[27] Wu Y.; Yang J.; Zhuang S.-Y.; Yu S.-B.; Zong Y.; Liu Y.-Y.; Wu G.; Qi Q.-Y.; Wang H.; Tian J.; Zhou W.; Ma D.; Zhang D.-W.; Li Z.-T.J. Med. Chem. 2024, 67, 2176.
[28] DiMaggio D.; Brockett A. T.; Shuster M.; Murkli S.; Zhai C.; King D.; O'Dowd B.; Cheng M.; Brady K.; Briken V.; Roesch M. R.; Isaacs L. ChemMedChem2022, 17, e202200046.
[29] Feng K.; Liu Y.-Y.; Yu C.; Zhu H.; Zong Y.; Lei Z.; Zhuang S.-Y.; Wu Y.; Yu S.-B.; Qi Q.-Y.; Tian J.; Zhou W.; Ma D.; Zhao G.; Xue X.-S.; Zhang D.-W.; Li, Z.-T. Sci. China Chem.2026, 69, 1331.
[30] Nair A.; Morsy M. A.; Jacob, S. Drug Dev. Res.2018, 79, 373.
[31] 徐叔云, 卞如濂, 陈修, 药理实验方法学, 人民卫生出版社, 北京, 2002, p. 214 (in Chinese)
(Xu S.; Bian R.; Chen X.Pharmacological Experimental Methodology, People's Medical Publishing House, Beijing, 2002, p. 214).
[32] Sridhar G. R.; Gumpeny, L. World J. Exp. Med.2024, 14, 87202.