Citation: Pei-Pei Liu, Jia-Bin Xing, Yue-Yang Liu, Ke Feng, Hui Wang, Dan-Wei Zhang, Wei Zhou, Gang Zhao, Jiaheng Zhang, Zhan-Ting Li. Sulfonatoproxylated cucurbit[7]urils as highly water-soluble and biocompatible excipients for solubilizing poorly soluble drugs and improving the bioavailability of indomethacin[J]. Chinese Chemical Letters, ;2025, 36(9): 110831. doi: 10.1016/j.cclet.2025.110831 shu

Sulfonatoproxylated cucurbit[7]urils as highly water-soluble and biocompatible excipients for solubilizing poorly soluble drugs and improving the bioavailability of indomethacin

Pei-Pei Liu ^a ,
Jia-Bin Xing ^a ,
Yue-Yang Liu ^a ,
Ke Feng ^b ,
Hui Wang ^a ,
Dan-Wei Zhang ^a ,
Wei Zhou ^{a, *,} ,
Gang Zhao ^c ,
Jiaheng Zhang ^{d, *,} ,
Zhan-Ting Li ^{a, b, *,}

a.
Department of Chemistry, Fudan University, Shanghai 200438, China
b.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200032, China
c.
School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, China
d.
Sauvage Laboratory for Smart Materials, Harbin Institute of Technology, Shenzhen 518055, China

zhouw@fudan.edu.cn

zhangjiaheng@hit.edu.cn

ztli@fudan.edu.cn

Received Date: 12 October 2024
Revised Date: 25 December 2024
Accepted Date: 6 January 2025
Available Online: 10 January 2025

Figures(4)

The ongoing development of small molecule drugs underscores the urgent need for novel excipients to formulate poorly soluble drug candidates. Cucurbit[7]uril (CB[7]) possesses high binding affinities for a variety of molecular guests. However, its moderate water solubility limits broader application. Here we report the synthesis of three CB[7] derivatives M1-M3 by modifying an average of 4.2, 5.5, and 5.9 sulfonatopropoxy groups onto their "equator" carbons. Compared to CB[7], their water-solubility increased by at least 26.6-, 23.6-, and 19.2-fold, respectively, while the maximum tolerated doses (MTD) of M1 and M2 improved by 2.5- and 2.3-fold. Phase solubility diagram studies demonstrate that M1 and M2 significantly enhance the water-solubility of eighteen poorly soluble drugs. In vivo experiments in rat complete Freund's arthritis reveal that M1 not only improves the anti-inflammatory efficacy of indomethacin by up to 52%, but also substantially reduces its side effect of gastric ulcer.
- Cucurbit[7]uril,
- Solubilization,
- Excipient,
- Host-guest chemistry,
- Molecular container,
- Indomethacin
1. [1]
  D.J. Cram, Angew. Chem. Int. Ed. 27 (1988) 1009–1020. doi: 10.1002/anie.198810093
2. [2]
  X. Ma, Y. Zhao, Chem. Rev. 115 (2015) 7794–7839. doi: 10.1021/cr500392w
3. [3]
  Y.L. Ma, S. Yan, X.J. Xu, H. Cao, R. Wang, Chin. Chem. Lett. 35 (2024) 108645. doi: 10.1016/j.cclet.2023.108645
4. [4]
  S. Liu, Y. Lin, D. Yan, Sci. China Chem. 66 (2023) 3532–3538. doi: 10.1007/s11426-023-1656-y
5. [5]
  G. Li, R.W. Lewis, R. Eelkema, CCS Chem. 6 (2024) 27–40. doi: 10.31635/ccschem.023.202303177
6. [6]
  Y.Y. Liu, X.Y. Yu, Y.C. Pan, et al., Sci. China Chem. 67 (2024) 1397–1441. doi: 10.1007/s11426-024-1971-4
7. [7]
  S.B. Yu, W. Zhou, J. Tian, et al., Sci. Sin. Chim. 53 (2023) 2345–2356. doi: 10.1360/SSC-2023-0134
8. [8]
  M. Inam, M.F. Sareh Sadat, W. Chen, Chem. Res. Chin. Univ. 39 (2023) 857–861. doi: 10.1007/s40242-023-3204-0
9. [9]
  Y. Sun, L. Jiang, Y. Chen, Y. Liu, Chin. Chem. Lett. 35 (2024) 108644. doi: 10.1016/j.cclet.2023.108644
10. [10]
  G. Crini, S. Fourmentin, É. Fenyvesi, et al., Environ. Chem. Lett. 16 (2018) 1361–1375. doi: 10.1007/s10311-018-0763-2
11. [11]
  V.J. Stella, R.A. Rajewski, Int. J. Pharm. 583 (2020) 119396. doi: 10.1016/j.ijpharm.2020.119396
12. [12]
  G.M. Keating, Drugs 76 (2016) 1041–1052. doi: 10.1007/s40265-016-0604-1
13. [13]
  M.V. Rekharsky, Y. Inoue, Chem. Rev. 98 (1998) 1875–1918. doi: 10.1021/cr970015o
14. [14]
  D.S. Guo, Y. Liu, Chem. Soc. Rev. 41 (2012) 5907–5921. doi: 10.1039/c2cs35075k
15. [15]
  Y.C. Pan, X.Y. Hu, D.S. Guo, Angew. Chem. Int. Ed. 60 (2021) 2768–2794. doi: 10.1002/anie.201916380
16. [16]
  P. Balaram, ACS Omega 9 (2024) 4162–4165. doi: 10.1021/acsomega.3c07196
17. [17]
  S.J. Barrow, S. Kasera, M.J. Rowland, J. del Barrio, O.A. Scherman, Chem. Rev. 115 (2015) 12320–12406. doi: 10.1021/acs.chemrev.5b00341
18. [18]
  T. Ogoshi, T.A. Yamagishi, Y. Nakamoto, Chem. Rev. 116 (2016) 7937–8002. doi: 10.1021/acs.chemrev.5b00765
19. [19]
  Z.D. Tang, X.M. Sun, T.T. Huang, et al., Chin. Chem. Lett. 34 (2023) 107698. doi: 10.1016/j.cclet.2022.07.041
20. [20]
  W. Yang, W. Zhang, J. Chen, J. Zhou, Chin. Chem. Lett. 35 (2024) 108740. doi: 10.1016/j.cclet.2023.108740
21. [21]
  H. Zhu, L. Chen, B. Sun, et al., Nat. Rev. Chem. 7 (2023) 768–782. doi: 10.1038/s41570-023-00531-9
22. [22]
  X.Y. Lou, S. Zhang, Y. Wang, Y.W. Yang, Chem. Soc. Rev. 52 (2023) 6644– 6663. doi: 10.1039/D3CS00506B
23. [23]
  G. Montà-González, E. Ortiz-Gómez, R. López-Lima, et al., Molecules 29 (2024) 1621. doi: 10.3390/molecules29071621
24. [24]
  Y. Zhang, G. Zhang, X. Xiao, Q. Li, Z. Tao, Coord. Chem. Rev. 514 (2024) 215889. doi: 10.1016/j.ccr.2024.215889
25. [25]
  M.W.Y. Southey, M. Brunavs, Front. Drug Discov. 3 (2023) 1314077. doi: 10.3389/fddsv.2023.1314077
26. [26]
  L. Di, P.V. Fish, T. Mano, Drug Discov. Today 17 (2012) 486–495. doi: 10.1016/j.drudis.2011.11.007
27. [27]
  K.I. Kuok, S. Li, I.W. Wyman, R. Wang, Ann. N. Y. Acad. Sci. 1398 (2017) 108–119. doi: 10.1111/nyas.13376
28. [28]
  J.J. Chu, M.G. Apps, N.J. Wheate, Supramol. Chem. 26 (2014) 648–656. doi: 10.1080/10610278.2014.926361
29. [29]
  X. Yang, Z. Wang, Y. Niu, et al., MedChemComm 7 (2016) 1392–1397. doi: 10.1039/C6MD00239K
30. [30]
  S. Li, J.Y.W. Chan, Y. Li, et al., Org. Biomol. Chem. 14 (2016) 7563–7569. doi: 10.1039/C6OB01060A
31. [31]
  Y. Wang, X. Yang, J. Luo, et al., Int. J. Pharm. 660 (2024) 124351. doi: 10.1016/j.ijpharm.2024.124351
32. [32]
  C.H.T. Kwong, J. Mu, S. Li, et al., Chin. Chem. Lett. 32 (2021) 3019–3022. doi: 10.1016/j.cclet.2021.04.008
33. [33]
  H.K. Liu, F. Lin, S.B. Yu, et al., J. Med. Chem. 65 (2022) 16893–16901. doi: 10.1021/acs.jmedchem.2c01677
34. [34]
  S.Y. Jon, N. Selvapalam, D.H. Oh, et al., J. Am. Chem. Soc. 125 (2003) 10186–10187. doi: 10.1021/ja036536c
35. [35]
  E.L. Robinson, P.Y. Zavalij, L. Isaacs, Supramol. Chem. 27 (2015) 288–297. doi: 10.1080/10610278.2014.940952
36. [36]
  V.D. Uzunova, C. Cullinane, K. Brix, W.M. Nau, A.I. Day, Org. Biomol. Chem. 8 (2010) 2037–2042. doi: 10.1039/b925555a
37. [37]
  P.S. Lee, J.Y. Han, T.W. Song, et al., Int. J. Pharm. 316 (2006) 29–36. doi: 10.1016/j.ijpharm.2006.02.035
38. [38]
  B. Zhang, P.Y. Zavalij, L. Isaacs, Org. Biomol. Chem. 12 (2014) 2413–2422. doi: 10.1039/C3OB42603C
39. [39]
  D. Ma, G. Hettiarachchi, D. Nguyen, et al., Nat. Chem. 4 (2012) 503–510. doi: 10.1038/nchem.1326
40. [40]
  B. Zhang, L. Isaacs, J. Med. Chem. 57 (2014) 9554–9563. doi: 10.1021/jm501276u
41. [41]
  K. Gou, X. Guo, Y. Wang, et al., Mater. Des. 214 (2022) 110359. doi: 10.1016/j.matdes.2021.110359
42. [42]
  J. Li, Y. Guo, H. Li, L. Shang, S. Li, Artif. Cells Nanomed. Biotechnol. 46 (2017) 1085–1094.
43. [43]
  J. Zhou, F. Zhu, J. Li, Y. Wang, Mater. Sci. Eng. C 90 (2018) 314–324. doi: 10.1016/j.msec.2018.04.071
44. [44]
  I. Sæbø, M. Bjørås, H. Franzyk, E. Helgesen, J. Booth, Int. J. Mol. Sci. 24 (2023) 2914. doi: 10.3390/ijms24032914
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  Jiarui Wu , Gengxin Wu , Yan Wang , Yingwei Yang . Crystal Engineering Based on Leaning Towerarenes. University Chemistry, 2024, 39(3): 58-62. doi: 10.3866/PKU.DXHX202304014
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