Citation: Ruxuan Wang, Rentao Zhang, Haoran Yang, Nina Xue, Xiaoguang Chen, Xiaoming Yu. Rational design, synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents[J]. Chinese Chemical Letters, ;2023, 34(2): 107529. doi: 10.1016/j.cclet.2022.05.043 shu

Rational design, synthesis, and biological evaluation of novel C6-modified geldanamycin derivatives as potent Hsp90 inhibitors and anti-tumor agents

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

angelnina@imm.ac.cn

chxg@imm.ac.cn

mingxyu@imm.ac.cn

Received Date: 18 February 2022
Revised Date: 10 May 2022
Accepted Date: 12 May 2022
Available Online: 20 May 2022

Figures(5)

Heat shock protein 90 (Hsp90) is an appealing anticancer drug target that provoked a tremendous wave of investigations. Geldanamycin (GA) is the first identified Hsp90 inhibitor that exhibited potent anti-cancer activity, but the off-target toxicity associated with the benzoquinone moiety hampered its clinical application. Until now, structure optimization of GA is still in need to fully exploit the therapeutic value of Hsp90. Due to the structural complexity and synthetic challenge of this compound family, conventional optimization is bound to be costly but high efficiency is expected to be reachable by combining the art of rational design and total synthesis. Described in this paper is our first attempt at this approach aiming at rational modification of the C6-position of GA. The binding affinities towards Hsp90 of compound 1 (C6-ethyl) and 2 (C6-methyl) were designed and predicted by using Discovery Studio. These compounds were synthesized and further subjected to a thorough in vitro biological evaluation. We found that compounds 1 and 2 bind to Hsp90 protein with the IC₅₀ of 34.26 nmol/L and 163.7 nmol/L, respectively. Both compounds showed broad-spectrum antitumor effects. Replacing by ethyl, compound 1 exhibited more potent bioactivity than positive control GA, such as in G2/M cell cycle arrest, cell apoptosis and client proteins degradations. The results firstly indicated that the docking study is able to provide a precise prediction of Hsp90 affinities of GA analogues, and the C6 substituent of GA is not erasable without affecting its biological activity.
- Hsp90 inhibitors,
- Geldanamycin derivatives,
- Total synthesis,
- Structure-activity relationship,
- Anticancer
1. [1]
  F. Ritossa, Cell Stress Chaperones 1 (1996) 97–98. doi: 10.1379/1466-1268(1996)001<0097:DOTHSR>2.3.CO;2
2. [2]
  M.Y. Xu, N.N. Xue, D. Liu, et al., Chinese Chem. Lett. 27 (2016) 11–15. doi: 10.1016/j.cclet.2015.09.024
3. [3]
  F.H. Schopf, M.M. Biebl, J. Buchner, Nat. Rev. Mol. Cell Biol. 18 (2017) 345–360. doi: 10.1038/nrm.2017.20
4. [4]
  D.F. Smith, L. Whitesell, S.C. Nair, et al., Mol. Cell. Biol. 15 (1995) 6804–6812. doi: 10.1128/MCB.15.12.6804
5. [5]
  L. Whitesell, E.G. Mimnaugh, B. De Costa, C.E. Myers, L.M. Neckers, Proc. Natl. Acad. Sci. U. S. A. 91 (1994) 8324–8328. doi: 10.1073/pnas.91.18.8324
6. [6]
  H.J. Ochel, T.W. Schulte, P. Nguyen, J. Trepel, L. Neckers, Mol. Genet. Metab. 66 (1999) 24–30. doi: 10.1006/mgme.1998.2774
7. [7]
  J. Trepel, M. Mollapour, G. Giaccone, L. Neckers, Nat. Rev. Cancer 10 (2010) 537–549. doi: 10.1038/nrc2887
8. [8]
  Y. Fukuyo, C.R. Hunt, N. Horikoshi, Cancer Lett. 290 (2010) 24–35. doi: 10.1016/j.canlet.2009.07.010
9. [9]
  G. Tudor, P. Gutierrez, A. Aguilera-Gutierrez, E.A. Sausville, Biochem. Pharmacol. 65 (2003) 1061–1075. doi: 10.1016/S0006-2952(03)00013-3
10. [10]
  J. Franke, S. Eichner, C. Zeilinger, A. Kirschning, Nat. Prod. Rep. 30 (2013) 1299–1323. doi: 10.1039/c3np70012g
11. [11]
  C. Bian, R. Yan, X. Yu, Tetrahedron 70 (2014) 2982–2991. doi: 10.1016/j.tet.2014.03.020
12. [12]
  Z. Zhang, N. Xue, C. Bian, et al., Bioorganic Med. Chem. Lett. 26 (2016) 4287–4291. doi: 10.1016/j.bmcl.2016.07.040
13. [13]
  L. Jin, R. Zhang, Z. Zhang, C. Bian, X. Yu, Tetrahedron Lett. 60 (2019) 547–551. doi: 10.1016/j.tetlet.2019.01.024
14. [14]
  Z. Zhang, Y. Li, R. Zhang, X. Yu, J. Org. Chem. 86 (2021) 15063–15075. doi: 10.1021/acs.joc.1c01582
15. [15]
  C.E. Stebbins, A.A. Russo, C. Schneider, et al., Cell 89 (1997) 239–250. doi: 10.1016/S0092-8674(00)80203-2
16. [16]
  R. Yan, C. Bian, X. Yu, Org. Lett. 16 (2014) 3280–3283. doi: 10.1021/ol5012899
17. [17]
  M.B. Andrus, E.J. Hicken, E.L. Meredith, B.L. Simmons, J.F. Cannon, Org. Lett. 5 (2003) 3859–3862. doi: 10.1021/ol035400g
18. [18]
  D.A. Evans, S.J. Miller, M.D. Ennis, P.L. Ornstein, J. Org. Chem. 57 (1992) 1067–1069. doi: 10.1021/jo00030a006
19. [19]
  T. Hosoya, E. Takashiro, T. Matsumoto, K. Suzuki, J. Am. Chem. Soc. 116 (1994) 1004–1015. doi: 10.1021/ja00082a023
20. [20]
  R. Baker, J.L. Castro, J. Chem. Soc. Perkin Trans. 1 (1990) 47–65.
21. [21]
  S. Ni, B. Jiang, L. Wu, et al., J. Antibiot. (Tokyo) 67 (2014) 183–185. doi: 10.1038/ja.2013.94
22. [22]
  N. Xue, J. Jin, D. Liu, et al., Curr. Cancer Drug Targets 14 (2014) 671–683. doi: 10.2174/1568009614666140908101523
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