Elsevier

Bioorganic & Medicinal Chemistry

Volume 18, Issue 24, 15 December 2010, Pages 8457-8462
Bioorganic & Medicinal Chemistry

Discovery of 1H-benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate as a potential antiproliferative agent by inhibiting histone deacetylase

https://doi.org/10.1016/j.bmc.2010.10.049Get rights and content

Abstract

Twenty-one benzotriazoles (316 and 1824) were synthesized and half of them (5, 816, 20, and 21) were reported for the first time. Their antiproliferative activities against three human cancer cells were assayed. It revealed that 1H-benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate (9) showed considerable activity against three human cancer cell lines with the half maximal inhibitory concentration (IC50) values of 1.2–2.4 nM, which were close to the value of the positive control, doxorubicin. Further investigation indicated compound 9 was a potential histone deacetylase inhibitor (IC50 = 9.4 μM) and its binding mode was simulated using docking method.

Introduction

Benzotriazole derivatives have been demonstrated to have an effect on cancer development. Steroidal C-17 benzoazoles inhibit the growth of prostate cancer cells.1 4,5,6,7-Tetrabromo-1H-benzotriazole (TBB) is a potent inhibitor of protein kinase CK2.2, 3 The complex [2-(4,5-dihydro-1H-imidazol-2-yl)-1H-benzotriazole]-dichlorocopper(II) shows very potent superoxide dismutase (SOD) activity and inhibits the growth of seven human tumor cell lines.4 A series of [4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids have been synthesized and tested as agonists of peroxisome proliferator-activated receptor (PPAR) γ, which has been demonstrated to inhibit growth and/or induce apoptosis in multiple cancer cell lines and in in vivo tumor models.5, 6 3-(1H-Benzo[d][1,2,3]triazol-1-yl)-1-(4-methoxyphenyl)-1-oxopropan-2-yl benzoate (BmOB) can inhibit proliferation of human hepatocarcinoma cells by increasing oxidative stress concomitant mitochondrial damage.7

On the other hand, histone deacetylase (HDAC) catalyzes the deacetylation of lysine (Lys) residues, predominantly in histones H3 and H4.8 Such chemical modification is one of the key steps in the regulation of expression of target genes affecting proper cell function, differentiation, and proliferation.9 Abnormal recruitment of HDACs has been clearly linked to carcinogenesis.10 Many compounds able to inhibit HDAC activity have been shown to have potent antitumor effect in vivo in tumor-bearing animals, and some of them are currently in phase I or phase I/II clinical trials.11

In this paper, we designed and synthesized 21 benzotriazole compounds bearing substituted benzoic acids and evaluated their antiproliferative activities. 1H-Benzo[d][1,2,3]triazol-1-yl 3,4,5-trimethoxybenzoate (9) showed the most potent activity and was further investigated its HDAC inhibitory activity. Docking simulation was also performed using X-ray crystallographic structure of the catalytic core of an archaebacterial HDAC homolog (histone deacetylase-like protein, HDLP), reported in 1999 by Finnin et al.12 to explore the binding modes of compound 9 at the active site. The results of this study may be useful to researchers attempting to find new potential antiproliferative agents.

Section snippets

Chemistry

Benzotriazole ring is the fundamental structure for the anticancer activities of benzotriazole derivatives. On the other hand, benzoic acid and its derivatives have wide biological activities, such as antimicrobials, antioxidant, and antitumor. Many of them have been used as active groups to designed anticancer drugs.13 In our previous work, we have also synthesized some potential lead compounds as antitumor agents deriving from substituted benzoic acids.14 Therefore, herein we tried to connect

Conclusions

Benzotriazoles 316 and 1824 were synthesized and evaluated their antiproliferative activities against three types of human cancer cell lines. Compound 9 showed the most potent activity with a mean IC50 of 1.7 nM. Further investigation of HDAC inhibitory activity showed that compound 9 was a potential HDAC inhibitor. Docking simulation of its binding mode was also carried out.

Chemistry general

All chemicals (reagent grade) used were purchased from Aldrich (USA). Separation of the compounds by column chromatography was carried out with silica gel 60 (200–300 mesh ASTM, E. Merck, Germany). The quantity of silica gel used was 50–100 times the weight charged on the column. Thin layer chromatography (TLC) was run on the silica gel coated aluminum sheets (silica gel 60 GF254, E. Merck, Germany) and visualized in ultraviolet (UV) light (254 nm). Melting points (uncorrected) were determined

Declaration

The material is original and has not been submitted for publication elsewhere. There is no conflict of interest in the manuscript. The main work in synthesis of benzotriazoles compounds, evaluation their biological activities, data analysis, and paper writing were finished by Jie Fu. Docking simulations was done by Ying Yang and Wen-Jun Mao. Xue-Wei Zhang and Zhi-Ming Zhang contributed to synthesis, biological assay, and data analysis. Hai-Liang Zhu is the corresponding author.

Acknowledgments

The authors are very grateful to the editor and anonymous reviewers for their invaluable comments and suggestions. The work was financed by the National Natural Science Foundation of China (no. 30772627) and Jiangsu National Science Foundation (no. BK2009239). The NMR spectra, EI-MS spectra and elementary analysis were measured at Center of Modern Analysis, Nanjing University. EI-MS spectra were determined at Medium Instrument Lab, School of Life Sciences, Nanjing University. The authors wish

References and notes (23)

  • S. Sarno et al.

    FEBS Lett.

    (2001)
  • S.S. Zhang et al.

    Eur. J. Pharmacol.

    (2008)
  • J.R. Davie

    Curr. Opin. Genet. Dev.

    (1998)
  • S. Vogel et al.

    Bioorg. Med. Chem.

    (2008)
  • Q.Z. Zheng et al.

    Bioorg. Med. Chem.

    (2010)
  • P. Bertrand

    Eur. J. Med. Chem.

    (2010)
  • G.J. Finlay et al.

    Anal. Biochem.

    (1984)
  • V.D. Handratta et al.

    J. Med. Chem.

    (2005)
  • M. Ruzzene et al.

    Biochem. J.

    (2002)
  • F. Saczewski et al.

    Arch. Pharm. (Weinh.)

    (2007)
  • A.E. Place et al.

    Clin. Cancer Res.

    (2003)
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