- Original article
- Open Access
Synthesis and evaluation of antitumor activities of novel chiral 1,2,4-triazole Schiff bases bearing γ-butenolide moiety
© Li et al.; licensee Springer. 2012
- Received: 9 November 2011
- Accepted: 26 February 2012
- Published: 3 July 2012
1,2,4-Triazole derivatives have received much attention due to their versatile biological properties including antibacterial, antifungal, anticonvulsant, antiinflammatory, anticancer, and antiproliferative properties. 1,2,4-Triazole nucleus has been incorporated into a wide variety of therapeutically interesting molecules to transform them into better drugs. Schiff bases of 1,2,4-triazoles have also been found to possess extensive biological activities. On the other hand, γ-substituted butenolide moiety represents a biological important entity that is present in numerous biologically active natural products.
We have described herein the synthesis of 12 hybrid 1,2,4-triazole Schiff bases bearing γ-substituted butenolide moiety. These compounds were synthesized by utilizing the tandem asymmetric Michael addition/elimination reaction as the key step. All the new compounds were evaluated for their in vitro anticancer activity.
Tandem asymmetric Michael addition/elimination approach has offered an easy access to new chiral 1,2,4-triazole compounds 7a-7l. All these chiral 1,2,4-triazole derivatives exhibited good anticancer activities towards Hela. Of all the tested compounds, the chiral compound 7l with an IC50 of 1.8 μM was found to be the most active.
- Schiff base
- A activity
- HeLa cells
Cancer, a diverse group of diseases characterized by the proliferation and spread of abnormal cells, is a major worldwide problem. Therefore, the discovery and development of new potent and selective anticancer drugs are of high importance in modern cancer research.
1,2,4-Triazole derivatives have received much attention due to their versatile biological properties including antibacterial, antifungal, anticonvulsant, antiinflammatory, anticancer, and antiproliferative properties [1–10]. 1,2,4-Triazole nucleus has been incorporated into a wide variety of therapeutically interesting molecules to transform them into better drugs [11–13]. Schiff bases of 1,2,4-triazoles have also been found to possess extensive biological activities [14–18]. On the other hand, γ-substituted butenolide moiety represents a biological important entity that is present in numerous biologically active natural products [19–24].
The enantiomerically pure γ-substituted butenolides 1 were synthesized via acetalization of mucobromic acid by employing (−)-menthol and (+)-borneol as a chiral auxiliary, respectively, and followed by resolution of the resulting diastereomers [25–27].
In vitro anticancer activities against HeLa cell lines with compounds 7a–l ( n = 3)
Growth inhibition rates of HeLa cell lines with compounds 7a–l at different concentrations
Inhibition rates (%)
All the chemicals were used as-received without further purification unless otherwise stated. IR spectra were recorded on a FTIR-8400S spectrometer as KBr disks. 1H NMR and 13 C NMR spectra were obtained with a Bruker Avance III 400 MHz spectrometer in chloroform-d (CDCl3) and tetramethylsilane was used as an internal standard. Diffraction measurement was made on a Bruker AXS SMART 1000 CCD diffractometer with graphite-monochromatized Mo Kα radiation (λ = 0.71073 Å). All the melting points were determined on a WRS-1B digital melting point apparatus and are uncorrected. Thin-layer chromatography (TLC) was carried out on silica GF254 plates (Qingdao Haiyang Chemical Co., Ltd., China).
General procedure for the synthesis of compounds 7
To an aqueous solution of dichloromethane was sequentially added the compounds 1 (1.0 mmol), potassium carbonate (1.0 mmol), 18-crown-6 (0.1 mmol), and the compounds 6 (1.1 mmol). The resulting mixture was stirred at room temperature, and the reaction was monitored by TLC. On completion of the reaction (10–20 h), the mixture was exacted and the organic layer was washed with saturated brine. Then the organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo The purification of the residue by silica gel column chromatography or crystallizations yielded the desired compounds 7a-l in 65-89% yields (For the characterization of compound 7a-7l, please see the Additional file 1: Supporting Information). Compound 7 l: white solid, 76% yield, [α]D 20 = −37.2 (c = 0.5 M, CHCl3). mp 131–132°C. IR (KBr) 3210, 1780, 1603, 1523, 1440, 1421, 1319, 1212, 1134, 993 cm-1. 1H NMR (400 MHz, CDCl3) 10.04 (s, 1H), 8.73 (s, 1H), 7.59-7.04 (m, 2H), 7.14-7.06 (m, 2H), 6.20 (s, 1H), 3.81 (m, 1H), 2.59 (s, 3H), 2.25-2.22 (m, 1H), 1.69-1.09 (m, 6H), 0.78-0.74 (m, 6H), 0.53 (s, 3H). 13 C NMR (100 MHz, CDCl3) 170.4, 164.0, 160.3, 152.9, 151.0, 138.2, 136.3, 133.7, 120.6, 118.1, 115.4, 112.8, 103.1, 88.8, 49.3, 47.6, 44.7, 36.7, 27.9, 26.5, 19.5, 18.7, 13.3, 11.2. HRMS calcd. for C24H27Br N4O4S [M]+: 546.0936, found 546.0933.
In summary, a new type of chiral 1,2,4-triazole Schiff bases bearing γ-substituted butenolide moiety have been synthesized and their in vitro anticancer activities against have been evaluated. These chiral 1,2,4-triazole derivatives exhibited good anticancer activities towards HeLa. The compound 7l with an IC50 of 1.8 μM was found to be the most active. Further studies of anticancer activities of these compounds are in progress in our group.
aThe molecular structure of the product 7a was determined by means of X-ray crystallographic studies. CCDC 829447 (7a) contains the supplementary crystallographic data for this article. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
We gratefully acknowledge the financial support from the National Natural Science Foundation of China (20962023, 21062014, 21162034), the Major State Basic Research Development Program of China (2007CB21602), the Program for New Century Excellent Talents in University (NCET-10-0907), the Key Project of Chinese Ministry of Education (210237), and the Natural Science Foundation of Ningxia Province of China (NZ0606).
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