Original article
In vitro and in vivo biological evaluation of new 4,5-disubstituted 1,2,3-triazoles as cis-constrained analogs of combretastatin A4

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Abstract

To find new and better antivascular agents for cancer therapy, a series of combretastatin A4 (CA4) analogs were prepared from 1,3-diaryl-2-nitroprop-1-enes (6–12) obtained in a two-step synthesis from appropriate arylaldehydes and 2-aryl-1-nitroethanes (4 or 5). Treatment of these 1,3-diaryl-2-nitroprop-1-enes 6–12 by sodium azide in DMSO yielded the targeted compounds. The synthesized 1,2,3-triazoles disubstituted in 4- and 5-positions by one benzyl group and one aryl nucleus have also been tested for biological activities involved in antivascular action. It was found that several new compounds exhibited interesting biological activities in the nanomolar or low micromolar range, in terms of rounding up of endothelial cells, inhibition of tubulin polymerization, and cytotoxicity on B16 melanoma cancer cells. In silico docking studies of 11 and 19 within the active site of tubulin were also carried out in order to rationalize the inhibitory properties of these compounds and further understand their inhibition mechanism. In vivo evaluation of compounds 11 and 19 in mice bearing colon 26 carcinoma indicated modest anticancer activity.

Graphical abstract

Amongst the synthesized compounds, the best rounding up activity was obtained with compounds 11 and 19 (R1 = R2 = R3 = R6 = OCH3, R4 = R5 = H, R7 = OH) with concentrations of 0.13 and 0.2 μM, respectively.

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Introduction

Tumor vasculature is an attractive target for cancer therapy because solid tumors require blood vessels to grow and metastasize [1], [2], [3], [4]. This requirement for neovascularization to allow tumors to grow beyond a certain threshold size drew attention to the potential therapeutic agents that may act on angiogenesis which occurs in several steps of the cancer process and offers several targets for intervention [1], [2], [3], [4], [5], [6], [7], [8], [9], [10].

Tumor vascularization is the result of pro-angiogenic factors and inhibitors and involves the interaction between endothelial cells and extracellular matrix. Various approaches have been developed to improve tumor control through the vascular targeting agents which can be divided into antiangiogenic and vascular-disrupting agents (VDAs) [11], [12], [13], [14].

Considering the VDAs [15], [16], the best active compounds that have been found to date are acting on tubulin polymerization. In this context, the molecule that emerged as one of the most potent is combretastatin A4 (CA4 1) which is a cis-stilbene derivative that was selected among seventeen combretastatin compounds originally isolated from the South African bushwillow tree Combretum caffrum Kuntze (Combretaceae) by Pettit and co-workers [17], [18], [19].

CA4 (1) is a strong inhibitor of tubulin polymerization and can induce an important cytotoxicity in the nanomolar range against various cancer cell lines, including multi-drug resistant ones [20]. To be active, 1 requires the cis-configuration, but it is known that it can easily isomerize into its trans inactive form [21], [22].

In order to stabilize the active configuration, numerous teams have synthesized a wide range of various cis-restricted analogs of 1. The literature has been repetitively reviewed during the past decade [23], [24], [25], [26], [27], [28], [29], [30], [31], [32] and, among the wide range of published heterocyclic compounds, the triazole derivatives have received little attention. In this context, some 3,4-disubstituted 1,2,4-triazole [33], [34], 1,4-disubstituted 1,2,3-triazole [35], [36], [37], [38], 1,5-disubstituted 1,2,3-triazole [36], [37], [38], [39], [40] and 4,5-disubstituted 1,2,3-triazole [40], [41], [42] showed interesting activities in terms of tubulin polymerization inhibition and/or cytotoxicity. To our knowledge, only one report [37] deals with triazoles having vicinal benzyl and phenyl substituents (in the relative 1,5-positions) designed in order to confer to the molecule a higher degree of conformational freedom.

In the context of hitherto unknown 1,2,3-triazoles disubstituted in the 4- and 5-positions by one aryl group and one benzyl substituent, the present study was undertaken to provide information on the biological activities of these compounds. We report here that several compounds of this series present interesting biological activities in the nanomolar or low micromolar range, in terms of rounding up of endothelial cells, inhibition of tubulin polymerization, and cytotoxicity on cancer cells. In silico docking studies of 11 and 19 within the active site of tubulin were also carried out and we also performed a preliminary in vivo evaluation of compounds 11 and 19 which revealed a modest anticancer activity in mice bearing colon 26 carcinoma tumors.

Section snippets

Chemistry

The title compounds were prepared starting from 1,3-diaryl-2-nitroprop-1-enes (6–12) obtained according to a procedure already described by one of us [43] from appropriate arylaldehydes and some 2-aryl-1-nitroethanes (4 or 5) by refluxing in toluene in the presence of dimethylammonium chloride and a small amount of potassium fluoride. The required nitro derivatives 4 and 5 were synthesized by a two-step procedure starting from suitable benzaldehydes via the corresponding 2-aryl-1-nitroethenes (2

Conclusion

We have, for the first time to our knowledge, synthesized new 1,2,3-triazoles disubstituted in 4- and 5-positions by one benzyl and one aryl groups. We also evaluated these new compounds for potential antivascular and anticancer activities and found that several compounds presented interesting biological activities, e.g., rounding up of endothelial cells (at concentrations in the submicromolar range), inhibition of tubulin polymerization and cytotoxicity on B16 cancer cells (at concentrations

Synthesis

Melting points were measured on a Köfler hot stage apparatus and are uncorrected. Mass spectra were recorded on a Waters ZQ 2000 system using electrospray ionization (ESI) or on a Waters LCT apparatus for High-resolution mass spectra (HRMS–ESI). Infrared spectra were obtained using an FT-IR Perkin–Elmer spectrometer as chloroform solutions or KBr discs. NMR spectra were recorded with a Bruker ACP 300 spectrometer at 300 MHz for 1H NMR and 75 MHz for 13C NMR. Chemical shifts are expressed as

Acknowledgments

This work was financially supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (Inserm), the Institut Curie and by a grant from the Institut National du Cancer (INCa, Boulogne Billancourt, France). We are also grateful to the University of Barcelone for a studentship (to Núria Mur Blanch).

References (67)

  • D.W. Siemann

    Cancer Treat. Rev.

    (2011)
  • K. Ohsumi et al.

    Bioorg. Med. Chem. Lett.

    (1998)
  • K. Odlo et al.

    Bioorg. Med. Chem.

    (2008)
  • K. Odlo et al.

    Bioorg. Med. Chem.

    (2010)
  • Ø.W. Akselsen et al.

    Bioorg. Med. Chem.

    (2012)
  • G. Jones et al.

    J. Mol. Biol.

    (1995)
  • R. Álvarez et al.

    Bioorg. Med. Chem.

    (2009)
  • A.K. Sinhababu et al.

    Tetrahedron Lett.

    (1983)
  • D. Bonne et al.

    J. Biol. Chem.

    (1985)
  • D.M. Barron et al.

    Anal. Biochem.

    (2003)
  • D.W. Siemann et al.

    Cancer

    (2004)
  • P.E. Thorpe

    Clin. Cancer Res.

    (2004)
  • D. Neri et al.

    Nat. Rev. Cancer

    (2005)
  • D.J. Chaplin et al.

    Curr. Opin. Investig. Drugs

    (2006)
  • C. Kanthou et al.

    Expert Opin. Ther. Targets

    (2007)
  • C.A. Honstvet et al.

    Comput. Math. Methods Med.

    (2007)
  • C. Kanthou et al.

    Int. J. Exp. Pathol.

    (2009)
  • V.L. Heath et al.

    Nat. Rev. Clin. Oncol.

    (2009)
  • M. Ham Fens et al.

    Expert Opin. Ther. Targets

    (2010)
  • L.G.M. Daenen et al.

    Curr. Clin. Pharmacol.

    (2010)
  • G.M. Tozer et al.

    Int. J. Exp. Pathol.

    (2002)
  • G.M. Tozer et al.

    Nat. Rev. Cancer

    (2005)
  • D.W. Siemann et al.

    Clin. Cancer Res.

    (2005)
  • R.S. Kerbel

    N. Engl. J. Med.

    (2008)
  • R.P. Mason et al.

    Integr. Biol.

    (2011)
  • G.R. Pettit et al.

    Can. J. Chem.

    (1982)
  • G.R. Pettit et al.

    J. Nat. Prod.

    (1987)
  • G.R. Pettit et al.

    Experientia

    (1989)
  • C.M. Lin et al.

    Mol. Pharmacol.

    (1988)
  • I.G. Kirwan et al.

    Clin. Cancer Res.

    (2004)
  • S. Aprile et al.

    Drug Metab. Dispos.

    (2007)
  • N.H. Nam

    Curr. Med. Chem.

    (2003)
  • A. Cirla et al.

    J. Nat. Prod. Rep.

    (2003)
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