Synthesis, characterization and anticancer evaluation of novel tri-arm star shaped 1,3,5-triazine hydrazones
Highlights
► Novel trisubstituted 1,3,5-triazine hydrazones synthesized. ► Structures of 1,3,5-triazine hydrazones are confirmed by spectroscopic techniques. ► In vitro antiproliferative activity was tested against HepG2 and HeLa cell lines.
Introduction
The synthetic utility and much of the industrial importance of triazine heterocycle arises from the ease by which nucleophilic aromatic substitutions occur on halogenated 1,3,5-triazines [1], [2]. In the synthesis of numerous compounds bearing the s-triazine core, 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) has been largely used as a starting material due to the ease of displacement of chlorine atoms by various nucleophiles. The systematic replacement of chlorine atoms under controlled temperature enhances the utility of this low-cost and readily available reagent for the preparation of mono-, di- and trisubstituted s-triazines [2], [3] and offers access to a multitude of useful molecules, from medicinal chemistry to materials [4], [5]. 1,3,5-Triazine-containing compounds are powerful chelating agents and have been used for the preparation of various metal complexes [6] and liquid crystals [7]. s-Triazine derivatives have proven their great potential in supramolecular chemistry [8]. Recently triazines have found extensive use as reagents in the conversion of functional groups [9]. Stepwise selective substitution pattern of cyanuric chloride is successfully utilized in the preparation of triazine based dendrimers [10].
In addition to the selective reactivity of three chlorine atoms of cyanuric chloride towards a variety of nucleophiles, the reaction of functional groups on the substituents attached to the 1,3,5-triazine ring system have drawn considerable interest. Recently hyperbranched polymers have been synthesized using the reactivity of peripheral functional groups on the aryl substituents appended on s-triazine AB2 type monomer structural units [11], [12]. 2,4,6-Tris(4-formylphenoxy)-1,3,5-triazine (Tripod) possessing three reactive peripheral aldehyde groups is used as a template for molecular imprinting of solid surfaces [13] and the synthesis of a three-helix bundle protein [14]. It is also used for immobilization of proteases [15]. Recently Tripod has been utilized for the preparation of Schiff bases [16], tripodal-benzimidazole [17] and star-shaped small monomer containing terminal cyanovinylene 4-nitrophenyls arms [18]. Although some examples of formation of thiosemicarbazones by the condensation of Tripod with thiosemicarbazides is described [19], to our knowledge formation of hydrazones by the reaction of aromatic hydrazides with Tripod has not been reported and deserves further exploration.
Hydrazones containing an azomethine (C(O)NHNCH) group are important synthons for several transformations and have gained importance due to their broad spectrum of biological activities [20], [21]. Aryl hydrazones and their metal complexes have attracted attention due to their therapeutic activity and application in materials research [22], [23]. Hydrazone linkage provides a suitable system for pH-dependent release of drugs from drug-conjugates [24]. Several hydrazide–hydrazone derivatives have been shown to exhibit antiproliferative activities and act as cytotoxic agents with the ability to prevent cell progression in cancerous cells through different mechanisms [25] and also exhibited antimicrobial [26], [27] and antitumoral [28] activities.
The triazine scaffold has provided basis for the design of biologically relevant molecules with broad biomedical value as therapeutics. It was reported that some of the triazine derivatives possess potent biological activity [29], [30], [31]. In continuation of our work on star shaped hydrazones [32], in this article we present the synthesis, characterization and in vitro anticancer efficacy of a series of s-1,3,5-triazine hydrazones prepared by the three-fold condensation of Tripod with p-substituted benzoic hydrazides against human liver carcinoma cell line (HepG2) and human cervix carcinoma cell line (HeLa).
Section snippets
Materials and measurements
IR spectra were recorded in KBr matrix using an Impact-410 Nicolet (USA) FT-IR spectrometer in 4000–400 cm−1 range. The 1H and 13C NMR spectra were recorded in DMSO-d6 solvent on BRUKER AV-400 MHz High Resolution Multinuclear FT-NMR Spectrometer at room temperature. The 1H and 13C NMR chemical shifts were measured using SiMe4 as an internal standard at δ = 0 ppm. In 1H NMR spectrum, DMSO-d6 solvent residual peak was observed at 2.49 ppm and water peak at 3.30 ppm. In 13C NMR spectrum DMSO-d6 solvent
Synthesis of tri-arm 1,3,5-triazine hydrazones
Tri-arm star shaped hydrazones with different substitutions at para positions emanating from 1,3,5-triazine core were synthesized as shown in Scheme 1. The initial reaction consists of grafting of three hydroxybenzaldehyde groups onto the 1,3,5-triazine core. The reaction of 2,4,6-trichloro-1,3,5-triazine with the sodium salt of 4-hydroxybenzaldehyde yielded 2,4,6-tris(4-formylphenoxy)-1,3,5-triazine. The second step consists of the condensation of 3 equivalents of benzoic hydrazides 2a–i with
Conclusion
A simple and convenient method for the synthesis of tri-arm star shaped molecules bearing hydrazone functions is reported. 2,4,6-Tris(4-formylphenoxy)-1,3,5-triazine (1) possessing three reactive terminal aldehydic functions on the substituents could be readily elaborated to the trifunctionalized hydrazones by condensation with the benzoic hydrazides. IR as well as 1H, 13C and 2D-HSQC NMR spectral characteristics of triazine hydrazones are consistent with their proposed structures. The 13C NMR
Acknowledgements
The authors thank the NMR Research Center, Indian Institute of Science, Bangalore, for NMR facility. Fellowship for S. S. Machakanur and B. R. Patil by the University Grants Commission under Research Fellowship in Sciences for Meritorious Students (UGC-RFSMS) is gratefully acknowledged. K. B. Gudasi is thankful to the Association of Commonwealth Universities, for Commonwealth fellowship.
References (41)
- et al.
- et al.
Inorg. Chim. Acta.
(2003) - et al.
Inorg. Chim. Acta.
(2007) Tetrahedron
(2006)- et al.
J. Hazardous Mater.
(2010) - et al.
Inorg. Chim. Acta.
(2009) - et al.
Adv. Drug Del. Rev.
(2004) - et al.
Bioorg. Med. Chem.
(2009) - et al.
Eur. J. Med. Chem.
(2002)
Bioorg. Med. Chem. Lett.
Eur. J. Med. Chem.
J. Mol. Struct.
Eur. J. Med. Chem.
J. Organomet. Chem.
J. Inorg. Biochem.
J. Immunol. Methods
Russ. Chem. Rev.
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