Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

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).
See this image and copyright information in PMC

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