Citation: Yuan Xiong, Lan-Hui Qin, Bei Zhao, Lei-Zhi Xu, Yu-Fan Fan, Tian Tian, Hai-Rong Zeng, Ting Liu, Jian Huang, Jian-Ming Sun, Zhen-Hao Tian, Guang-Bo Ge. Structure-based design and development of halogenated-naphthalimides as potent hCYP1B1 inhibitors for overcoming paclitaxel resistance[J]. Chinese Chemical Letters, ;2025, 36(11): 110812. doi: 10.1016/j.cclet.2024.110812 shu

Structure-based design and development of halogenated-naphthalimides as potent hCYP1B1 inhibitors for overcoming paclitaxel resistance

Yuan Xiong ^{a, b, 1} ,
Lan-Hui Qin ^{a, 1} ,
Bei Zhao ^a ,
Lei-Zhi Xu ^a ,
Yu-Fan Fan ^a ,
Tian Tian ^a ,
Hai-Rong Zeng ^a ,
Ting Liu ^f ,
Jian Huang ^{e, *,} ,
Jian-Ming Sun ^{b, *,} ,
Zhen-Hao Tian ^{c, d, *,} ,
Guang-Bo Ge ^{a, *,}

a.
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
b.
Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China
c.
School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China
d.
Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment, Xi'an 710072, China
e.
Pharmacology and Toxicology Division, Shanghai Institute of Food and Drug Control, Shanghai 201203, China
f.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China

m13917109448@163.com

sunjm67@126.com

zhhtian@nwpu.edu.cn

geguangbo@shutcm.edu.cn

Received Date: 30 September 2024
Revised Date: 29 December 2024
Accepted Date: 30 December 2024
Available Online: 31 December 2024

Figures(4)

Human cytochrome P450 1B1 (hCYP1B1), an extrahepatic heme-dependent monooxygenase, has been validated as a key target for overcoming chemotherapy resistance and tumorigenesis. Herein, to discover novel efficacious hCYP1B1 inhibitors, a suite of 1,8-naphthalimide derivatives was designed, synthesized, and biologically evaluated, via integrating structure-based drug design (SBDD) and biochemical assays. After two rounds of structural modifications and structure-activity relationship (SAR) studies, the results suggested that introducing a benzene ring at the north part and a halogen atom at the C-4 site significantly enhanced the anti-hCYP1B1 effects of naphthalimides. Among all tested 1,8-naphthalimides, NB-10 showed the most potent anti-hCYP1B1 effect (half maximal inhibitory concentration (IC₅₀) = 0.41 nmol/L) and excellent specificity, while this agent did not activate AhR transcription activity in living cells. Further cellular assays and in vivo tests in paclitaxel (PTX)-resistance xenograft mice showed that NB-10 could significantly potentiate the anti-cancer effects of PTX both in vitro and in vivo, while this agent also showed high safety profiles in mice. Mechanistically, NB-10 potently inhibited hCYP1B1-catalyzed 7-ethoxyresorufin O-deethylation in a competitive manner, with an estimated K_i value of 0.15 nmol/L. Docking simulations showed that NB-10 could be well-fitted in the catalytic pocket of hCYP1B1 to form a stable conformation with a high binding affinity. Collectively, several potent 4-halogenated naphthalimides were developed as novel hCYP1B1 inhibitors, while NB-10 showed high safety profiles and impressive efficacy for overcoming hCYP1B1-associated PTX resistance both in vitro and in vivo.
1. [1]
  G.I. Murray, W.T. Melvin, W.F. Greenlee, M.D. Burke, Annu. Rev. Pharmacol. Toxicol. 41 (2001) 297–316. doi: 10.1146/annurev.pharmtox.41.1.297
2. [2]
  V.P. Androutsopoulos, I. Spyrou, A. Ploumidis, et al., PLoS One 8 (2013) e82487. doi: 10.1371/journal.pone.0082487
3. [3]
  Q. Shen H. Zhou, J. Fu, et al., J Clin. Lab. Anal. 34 (2020) e23312. doi: 10.1002/jcla.23312
4. [4]
  J.J. Wu, X.Q. Guan, Z.R. Dai, et al., Coordin. Chem. Rev. 427 (2021) 213600. doi: 10.1016/j.ccr.2020.213600
5. [5]
  Z. Dai, Y. Wu, Y. Xiong, Med. Res. Rev. 44 (2024) 169–234. doi: 10.1002/med.21982
6. [6]
  R. Dutour, D. Poirier, Eur. J. Med. Chem. 135 (2017) 296–306. doi: 10.1016/j.ejmech.2017.04.042
7. [7]
  X. Mao, H. Li, J. Zheng, Drug. Metab. Rev. 55 (2023) 1–49. doi: 10.1080/03602532.2023.2177671
8. [8]
  T. Shimada, Drug. Metab. Pharmacokinet. 21 (2006) 257–276. doi: 10.2133/dmpk.21.257
9. [9]
  S. Sinha, S. Aizawa, Y. Nakano, et al., Nat. Commun. 14 (2023) 2651. doi: 10.1038/s41467-023-38406-8
10. [10]
  Y.J. Kwon, S. Shin, Y.J. Chun, Arch. Pharm. Res. 44 (2021) 63–83. doi: 10.1007/s12272-021-01306-w
11. [11]
  L. Umannová, M. Machala, J. Topinka, et al., Mutat. Res. 640 (2008) 162–169. doi: 10.1016/j.mrfmmm.2008.02.001
12. [12]
  O. Hankinson, Drug. Metab. Rev. 48 (2016) 342–350. doi: 10.1080/03602532.2016.1197240
13. [13]
  T.M. Sissung, D.K. Price, A. Sparreboom, et al., Mol. Cancer Res. 4 (2006) 135–150. doi: 10.1158/1541-7786.MCR-05-0101
14. [14]
  F. Li, W. Zhu, F.J. Gonzalez, Pharmacol. Ther. 178 (2017) 18–30. doi: 10.1016/j.pharmthera.2017.03.007
15. [15]
  M.C. McFadyen, M.E. Cruickshank, I.D. Miller, et al., Br. J. Cancer 85 (2001) 242–246. doi: 10.1054/bjoc.2001.1907
16. [16]
  G.D. '. Uva, D. Baci, A. Albini, et al., Cancer Treat. Rev. 63 (2018) 1–18. doi: 10.1016/j.ctrv.2017.10.013
17. [17]
  J. Mao, D. Wang, P. Xu, et al., J. Med. Chem. 65 (2022) 16451–16480. doi: 10.1021/acs.jmedchem.2c01306
18. [18]
  V.R. Sonawane, M.U.M. Siddique, L. Gatchie, et al., Eur. J. Pharm. Sci. 131 (2019) 177–194. doi: 10.1016/j.ejps.2019.02.016
19. [19]
  B. Yuan, G. Liu, Z. Dai, et al., Cancers 14 (2022) 5641. doi: 10.3390/cancers14225641
20. [20]
  Y. Xue, T. Yin, S. Yuan, et al., Drug Resist. Updat. 77 (2024) 101151. doi: 10.1016/j.drup.2024.101151
21. [21]
  C. Chen, Y. Yang, Y. Guo, et al., Cell. Death. Dis. 14 (2023) 271. doi: 10.1038/s41419-023-05803-2
22. [22]
  L. Zhou, W. Chen, C. Cao, et al., Eur. J. Med. Chem. 189 (2020) 112028. doi: 10.1016/j.ejmech.2019.112028
23. [23]
  P. Chen, S. Wang, C. Cao, et al., Bioorg. Chem. 116 (2021) 105295. doi: 10.1016/j.bioorg.2021.105295
24. [24]
  J. Wu, W. Jia, D. Min, et al., Am. J. Chin. Med. 52 (2024) 2403–2421. doi: 10.1142/S0192415X24500915
25. [25]
  J. Cui, Q. Meng, X. Zhang, et al., J. Med. Chem. 58 (2015) 3534–3547. doi: 10.1021/acs.jmedchem.5b00265
26. [26]
  J.Y. Dong, G. Huang, Q. Cui, et al., Eur. J. Med. Chem. 209 (2021) 112895. doi: 10.1016/j.ejmech.2020.112895
27. [27]
  A.C. Hachey, A.D. Fenton, D.K. Heidary, et al., J. Med. Chem. 66 (2023) 398–412. doi: 10.1021/acs.jmedchem.2c01368
28. [28]
  J.Y. Dong, Q. Zhang, Q. Cui, et al., ChemMedChem 11 (2016) 2102–2118. doi: 10.1002/cmdc.201600316
29. [29]
  F. Zhang, B. Zhao, Y.F. Fan, et al., Acta Pharmacol. Sin. B 15 (2025) 508–525. doi: 10.1016/j.apsb.2024.09.014
30. [30]
  J. Liu, J. Sridhar, M. Foroozesh, Molecules 18 (2013) 14470–14495. doi: 10.3390/molecules181214470
31. [31]
  M. Parekh, Y. Adhikari, N. Deshpande, et al., Exp. Eye Res. 248 (2024) 110089. doi: 10.1016/j.exer.2024.110089
32. [32]
  A.G. Bart, K.L. Harris, E.M.J. Gillam, et al., J. Biol. Chem. 295 (2020) 5640–5653. doi: 10.1074/jbc.RA119.010727
33. [33]
  E.F. Johnson, C.D. Stout, J. Biol. Chem. 288 (2013) 17082–17090. doi: 10.1074/jbc.R113.452805
34. [34]
  R.S. Ferreira, A.D. Andricopulo, Curr. Pharm. Des. 20 (2014) 687–693. doi: 10.2174/138161282005140214161949
35. [35]
  G.F. Hao, G.F. Yang, C.G. Zhan, Drug. Discov. Today 17 (2012) 1121–1126. doi: 10.1016/j.drudis.2012.06.018
36. [36]
  J.Y. Lee, H. Cho, S. Thangapandian, et al., ACS Med. Chem. Lett. 9 (2018) 1247–1252. doi: 10.1021/acsmedchemlett.8b00409
37. [37]
  J.Y. Dong, Z.T. Wang, J. Cui, et al., Eur. J. Med. Chem. 187 (2020) 111938. doi: 10.1016/j.ejmech.2019.111938
38. [38]
  E. Berrino, B. Michelet, A. Martin-Mingot, et al., Angew. Chem. Int. Ed. 60 (2021) 23068–23082. doi: 10.1002/anie.202103211
39. [39]
  E.P. Gillis, K.J. Eastman, M.D. Hill, et al., J. Med. Chem. 58 (2015) 8315–8359. doi: 10.1021/acs.jmedchem.5b00258
40. [40]
  V. Govindaraj, H. Ungati, S.R. Jakka, et al., Chemistry 25 (2019) 11180–11192. doi: 10.1002/chem.201902243
41. [41]
  L.M. Zhao, C. Pannecouque, E.D. Clercq, et al., Chin. Chem. Lett. 34 (2023) 108261. doi: 10.1016/j.cclet.2023.108261
42. [42]
  S.K. Gupta, A. Mandal, A. Ghosh, et al., Sci. Rep. 14 (2024) 28045. doi: 10.1038/s41598-024-77236-6
43. [43]
  M. Wang, N. Luo, Y. Gao, et al., Sci. Total. Environ. 916 (2024) 170030. doi: 10.1016/j.scitotenv.2024.170030
44. [44]
  T. Yang, Y.L. Feng, L. Chen, et al., Crit. Rev. Toxicol. 49 (2019) 445–460. doi: 10.1080/10408444.2019.1635987
45. [45]
  L. Lin, Y. Dai, Y. Xia, Eur. J. Med. Chem. 244 (2022) 114845. doi: 10.1016/j.ejmech.2022.114845
46. [46]
  R. He, Z. Dai, M. Finel, et al., Drug. Metab. Dispos. 10 (2023) 1254–1272.
47. [47]
  Y. Yang, Y. Xiong, G. Zhu, et al., Chem. Biol. Interact. 378 (2023) 110501. doi: 10.1016/j.cbi.2023.110501
48. [48]
  F. Zhang, W. Liu, J. Huang, et al., Acta Pharmacol. Sin. 43 (2022) 1072–1081. doi: 10.1038/s41401-021-00697-2
49. [49]
  Y. Wu, J.H. Shi, G.H. Zhu, et al., Eur. J. Med. Chem. 258 (2023) 115552. doi: 10.1016/j.ejmech.2023.115552
50. [50]
  A. Daina, O. Michielin, V. Zoete, et al., Sci. Rep. 7 (2017) 42717. doi: 10.1038/srep42717
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2. [2]
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