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. 2021 May 25;26(11):3162.
doi: 10.3390/molecules26113162.

Synthesis and Biological Evaluation of Spirocyclic Chromane Derivatives as a Potential Treatment of Prostate Cancer

Li Feng  1   2 , Shujia Yu  2 , Hai Wang  2 , Shengwei Yang  2 , Xue Li  2 , Hongjuan Dai  3 , Liwen Zhao  2 , Cheng Jiang  1 , Yazhou Wang  2
Affiliations

Synthesis and Biological Evaluation of Spirocyclic Chromane Derivatives as a Potential Treatment of Prostate Cancer

Li Feng et al. Molecules. .

Abstract

As a significant co-activator involved in cell cycle and cell growth, differentiation and development, p300/CBP has shown extraordinary potential target in cancer therapy. Herein we designed new compounds from the lead compound A-485 based on molecular dynamic simulations. A series of new spirocyclic chroman derivatives was prepared, characterized and proven to be a potential treatment of prostate cancer. The most potent compound B16 inhibited the proliferation of enzalutamide-resistant 22Rv1 cells with an IC50 value of 96 nM. Furthermore, compounds B16-P2 displayed favorable overall pharmacokinetic profiles, and better tumor growth inhibition than A-485 in an in vivo xenograft model.

Keywords: HAT inhibitors; antitumor activity; p300/CBP.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Representative small-molecule p300/CBP HAT inhibitors 1–8.
Figure 2
Figure 2
Molecular dynamics simulation and analysis of the interaction of A-485 with p300/CBP HAT domain. (A) RMSD of HAT backbone during the simulation time. (B) The residue contribution for protein-ligand interaction (blue: hydrogen bonds; purple: hydrophobic contacts). (C) Surface and interaction of the complex. (PDB code: 5kj2).
Figure 3
Figure 3
Current main design of new spirocyclic derivatives (P, Q = CH, N).
Scheme 1
Scheme 1
Reagents and conditions: (a) TMSCN, NMO, acetonitrile, 60 °C, 81%; (b) AcCl, EtOH, 76%; (c) 1-(bromomethyl)-4-fluorobenzene, trifluoroacetic acid, triphosgene, THF, 10 °C, 93%; (d) K2CO3, DMF, 30 °C, 47%; (e) bromoacetyl bromide, methylene chloride, 39%; (f) K2CO3, DMF, 42%; (g) Pd(dppf)Cl2, NaHCO3, 1,4-dioxane, 85 °C, 33%.
Figure 4
Figure 4
In vivo 22Rv1 xenograft model study of compound B16-P2 and A-485. (A) The tumor growth curve of four groups. (B) The body weights of mice over time (n = 6, * p < 0.05 versus control).
Figure 5
Figure 5
Docking mode of compound B16 (coppery) with p300 HAT domain overlapping with A-485 (green) (PDB code: 5kj2).
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References

    1. Jones P.A., Baylin S.B. The epigenomics of cancer. Cell. 2007;128:683–692. doi: 10.1016/j.cell.2007.01.029. - DOI - PMC - PubMed
    1. Haberland M., Montgomery R., Olson E. The many roles of histone deacetylases in development and physiology: Implications for disease and therapy. Nat. Rev. Genet. 2009;10:32–42. doi: 10.1038/nrg2485. - DOI - PMC - PubMed
    1. Tessarz P., Kouzarides T. Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell. Biol. 2014;15:703–708. doi: 10.1038/nrm3890. - DOI - PubMed
    1. Wu J., Xie N., Wu Z., Zhang Y., Zheng Y.G. Bisubstrate inhibitors of the MYST HATs Esa1 and Tip60. Bioorg. Med. Chem. 2009;17:1381–1386. doi: 10.1016/j.bmc.2008.12.014. - DOI - PubMed
    1. Farria A., Li W., Dent S. KATs in cancer: Functions and therapies. Oncogene. 2015;34:4901–4913. doi: 10.1038/onc.2014.453. - DOI - PMC - PubMed