|
|
Novel hybrids from N-hydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities |
Mao Caia, Jie Hub, Ji-Lai Tianc, Huang Yana, Chen-Guo Zhenga, Wan-Le Hua |
a Department of Coloproctology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China;
b Department of Pharmacy, Wenzhou Medical University, Wenzhou 325000, China;
c Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210008, China |
|
|
Abstract Novel hybrid molecules 8a-8o were designed and synthesized by connecting indole ring with N-hydroxyarylamide through alkyl substituted triazole, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed promising anticancer activities, particularly for 8n, which had a significant HDACs inhibitory and antiproliferative activities comparable to or slightly stronger than SAHA against human carcinoma cells. Furthermore, compound 8n exhibited much better selectivity for HDAC1 over HDAC6 and HDAC8 than SAHA. In addition, compound 8n also could dose-dependently induce cancer cell cycling arrest at G0/G1 phase and promote the expression of the acetylation for histone H3 and tubulin in vitro. Therefore, our novel findings may provide a new framework for the design of new selective HDAC inhibitor for the treatment of cancer.
|
Received: 11 December 2014
Published: 27 March 2015
|
Corresponding Authors:
Wan-Le Hua
E-mail: wanlehu@163.com
|
|
|
|
[1] |
Z. Li, W.G. Zhu, Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications, Int. J. Biol. Sci. 10 (2014) 757-770.
|
[2] |
C.B. Yoo, P.A. Jones, Epigenetic therapy of cancer: past, present and future, Nat. Rev. Drug Discov. 5 (2006) 37-50.
|
[3] |
L. Simó-Riudalbas, M. Esteller, Targeting the histone orthography of cancer: drugs for writers, erasers and readers, Br, J. Pharmacol. 172 (2015) 2716-2732.
|
[4] |
H. Lehrmann, L.L. Pritchard, A. Harel-Bellan, et al., Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation, Adv. Cancer Res. 86 (2002) 41-65.
|
[5] |
B.E. Bernstein, J.K. Tong, S.L. Schreiber, Genome wide studies of histone deacetylase function in yeast, Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 13708-13713.
|
[6] |
O. Witt, H.E. Deubzer, T. Milde, I. Oehme, et al., HDAC family: what are the cancer relevant targets, Cancer Lett. 277 (2009) 8-21.
|
[7] |
P. Bose, Y. Dai, S. Grant, Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights, Pharmacol. Ther. 143 (2014) 323-336.
|
[8] |
A.C. West, R.W. Johnstone, New and emerging HDAC inhibitors for cancer treatment, J. Clin. Invest. 124 (2014) 30-39.
|
[9] |
M. Slingerland, H.J. Guchelaar, H. Gelderblom, Histone deacetylase inhibitors: an overview of the clinical studies in solid tumors, Anticancer Drugs 25 (2014) 140-149.
|
[10] |
P.A. Marks, Discovery and development of SAHA as an anticancer agent, Oncogene 26 (2007) 1351-1356.
|
[11] |
FK228: http://www.fda.gov/NewsEvents/Newsroom/Press Announcements/2009/ucm189629.htm.
|
[12] |
T. Qiu, L. Zhou, W. Zhu, et al., Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials, Future Oncol. 9 (2013) 255-269.
|
[13] |
T. You, K. Chen, F.H. Wang, et al., Design, synthesis, and biological evaluation of Nhydroxycinnamamide/salicylic acid hybrids as histone deacetylase inhibitors, Chin. Chem. Lett. 25 (2014) 474-478.
|
[14] |
T.A. Miller, D.J. Witter, S. Belvedere, Histone deacetylase inhibitors, J. Med. Chem. 46 (2003) 5097-5116.
|
[15] |
P.A. Marks, The clinical development of histone deacetylase inhibitors as targeted anticancer drugs, Expert Opin. Invest. Drugs 19 (2010) 1049-1066.
|
[16] |
J. McDermott, A. Jimeno, Belinostat for the treatment of peripheral T-cell lymphomas, Drugs Today (Barc.) 50 (2014) 337-345.
|
[17] |
W.P. Yong, B.C. Goh, R.A. Soo, et al., Phase I and pharmacodynamic study of an orally administered novel inhibitor of histone deacetylases, SB939, in patients with refractory solid malignancies, Ann. Oncol. 22 (2011) 2516-2522.
|
[18] |
J.S. de Bono, R. Kristeleit, A. Tolcher, et al., Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors, Clin. Cancer Res. 14 (2008) 6663-6673.
|
[19] |
S. Fouliard, R. Robert, A. Jacquet-Bescond, et al., Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I, Eur. J. Cancer 49 (2013) 2791-2797.
|
[20] |
A. Furlan, V. Monzani, L.L. Reznikov, et al., Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat), Mol. Med. 17 (2011) 353-362.
|
[21] |
Ø. Bruserud, C. Stapnes, E. Ersvaer, et al., Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell, Curr. Pharm. Biotechnol. 8 (2007) 388-400.
|
[22] |
J. Amato, N. Iaccarino, B. Pagano, et al., Bis-indole derivatives with antitumor activity turn out to be specific ligands of human telomeric G-quadruplex, Front. Chem. 2 (2014) 54.
|
[23] |
M.T. Macdonough, T.E. Strecker, E. Hamel, et al., Synthesis and biological evaluation of indole-based, anti-cancer agents inspired by the vascular disrupting agent 2-(30-hydroxy-40-methoxyphenyl)-3-(300,400,500-trimethoxybenzoyl)-6-methoxyindole (OXi8006), Bioorg. Med. Chem. 21 (2013) 6831-6843.
|
[24] |
Y.S. Cho, L. Whitehead, J. Li, et al., Conformational refinement of hydroxamatebased histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824), J. Med. Chem. 53 (2010) 2952-2963.
|
[25] |
C.D. Hein, X.M. Liu, D. Wang, Click chemistry, a powerful tool for pharmaceutical sciences, Pharm. Res. 25 (2008) 2216-2230.
|
[26] |
G.C. Tron, T. Pirali, R.A. Billington, et al., Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes, Med. Res. Rev. 28 (2008) 278-308.
|
[27] |
A.R. Bogdan, K. James, Efficient access to new chemical space through flowconstruction of druglike macrocycles through copper-surface-catalyzed azidealkyne cycloaddition reactions, Chemistry 16 (2010) 14506-14512.
|
|
|
|