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.
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].
Results and discussion
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.
Supporting information available
Experimental procedures, spectral data of new compounds.
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).
- Sztanke K, Tuzimski T, Rzymowska J, Pasternak K, Kandefer-Szerszen M: Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazolederivatives. Eur J Med Chem 2008, 43: 404–419. 10.1016/j.ejmech.2007.03.033View ArticleGoogle Scholar
- Sadana AK, Mirza Y, Aneja KR, Prakash O: Hypervalent iodine mediated synthesis of 1-aryl/hetryl-1,2,4-triazolo[4,3-a]pyridines and 1-aryl/hetryl5-methyl-1,2,4-triazolo[4,3-a]quinolines as antibacterial agents. Eur J Med Chem 2003, 38: 533–536. 10.1016/S0223-5234(03)00061-8View ArticleGoogle Scholar
- Amir M, Kumar H, Javed SA: Condensed bridge head nitrogen heter-ocyclic system: synthesis and pharmacological activities of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives of ibuprofen and biphenyl-4-yloxyaceticacid. Eur Med Chem 2008, 43: 2056–2066. 10.1016/j.ejmech.2007.09.025View ArticleGoogle Scholar
- Turan-Zitouni G, Kaplancıklı ZA, Yıldız MT, Chevallet P, Kaya D: Synthesis and antimicrobial activity of 4-phenyl/cyclohexyl-5-(1-phenoxyethyl)-3-[N-(2-thiazolyl)acetamido]thio-4H-1,2,4-triazole derivatives. Eur J Med Chem 2005, 40: 607–613. 10.1016/j.ejmech.2005.01.007View ArticleGoogle Scholar
- Mavrova AT, Wesselinova D, Tsenov YA, Denkova P: Synthesis, cytotoxicity and effects of some1,2,4-triazole and 1,3,4-thiadiazole derivatives on immunocompetent cells. Eur J Med Chem 2009, 44: 63–69. 10.1016/j.ejmech.2008.03.006View ArticleGoogle Scholar
- Al-Soud YA, Al-Masoudi NA, Ferwanah AE-RS: Synthesis and properties of new substituted 1,2,4-triazoles: potential antitumor agents. Bioorg Med Chem 2003, 11: 1701–1708. 10.1016/S0968-0896(03)00043-9View ArticleGoogle Scholar
- Almasirad A, Tabatabai SA, Faizi M, Kebriaeezadeh A, Mehrabi N, Dalvandi A, Shafiee A: Synthesis and anticonvulsant activity of new 2-substituted-5-[2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg Med Chem Lett 2004, 14: 6057–6059. 10.1016/j.bmcl.2004.09.072View ArticleGoogle Scholar
- Padmavathi V, Thriveni P, Reddy GS, Deepti D: Synthesis and antimicrobial activity of novel sulfone-linked bis heterocycles. Eur J Med Chem 2008, 43: 917–924. 10.1016/j.ejmech.2007.06.011View ArticleGoogle Scholar
- Bhat KS, Poojary B, Prasad DJ, Naik P, Holla BS: Synthesis and antitumor activity studies of some new fused 1,2,4-triazole derivatives carrying 2,4-dichloro-5-fluorophenylmoiety. Eur J Med Chem 2009, 44: 5066–5070. 10.1016/j.ejmech.2009.09.010View ArticleGoogle Scholar
- Romagnoli R, Baraldi PG, Cruz-Lopez O, Cara CL, Carrion MD, Brancale A, Hamel E, Chen L, Bortolozzi R, Basso G, Viola G: Synthesis and antitumor activity of 1,5-disubstituted 1,2,4-triazoles as cis-restricted combretastatin analogues. J Med Chem 2010, 53: 4248–4258. 10.1021/jm100245qView ArticleGoogle Scholar
- Sun S, Lou H, Gao Y, Fan P, Ma B, Ge W, Wang X: Liquid chromatography-tandem mass spectrometric method for the analysis of fluconazole and evaluation of the impact of phenolic compounds on the concentration of fluconazole in Candida albicans. J Pharm Biomed Anal 2004, 34: 1117–1124. 10.1016/j.jpba.2003.11.013View ArticleGoogle Scholar
- Clemons M, Coleman RE, Verma S: Aromatase inhibitors in the adjuvant setting: bringing the gold to a standard. Cancer Treat Rev 2004, 30: 325–332. 10.1016/j.ctrv.2004.03.004View ArticleGoogle Scholar
- Johnston GAR: Medicinal chemistry and molecular pharmacology of GABAC receptors. Curr Top Med Chem 2002, 2: 903–913. 10.2174/1568026023393453View ArticleGoogle Scholar
- Li Z, Gu Z, Yin K, Zhang R, Deng Q, Xiang J: Synthesis of substituted-phenyl-1,2,4-triazol-3-thione analogues with modified d-glucopyranosyl residues and their antiproliferative activities. Eur J Med Chem 2009, 44: 4716–4720. 10.1016/j.ejmech.2009.05.030View ArticleGoogle Scholar
- Holla BS, Veerendra B, Shivananda MK, Poojary B: Synthesis characterization and anticancer activity studies on some Mannich bases derived from 1,2,4-triazoles. Eur J Med Chem 2003, 38: 759–767. 10.1016/S0223-5234(03)00128-4View ArticleGoogle Scholar
- Bayrak H, Demirbas A, Karaoglu SA, Demirbas N: Synthesis of some new 1,2,4-triazoles, their Mannich and Schiff bases and evaluation of their antimicrobial activities. Eur J Med Chem 2009, 44: 1057–1066. 10.1016/j.ejmech.2008.06.019View ArticleGoogle Scholar
- Bagihalli GB, Avaji PG, Patil SA, Badami PS: Synthesis, spectra characterization, in vitro anti bacterial, antifungal and cytotoxic activities of Co(II), Ni(II) and Cu(II) complexes with 1,2,4-triazole Schiff bases. Eur J Med Chem 2008, 43: 2639–2649. 10.1016/j.ejmech.2008.02.013View ArticleGoogle Scholar
- Bekircan O, Bektas H: Synthesis of new bis-1,2,4-triazole derivatives. Molecules 2006, 11: 469–477. 10.3390/11060469View ArticleGoogle Scholar
- Gunasekera SP, McCarthy PJ, Kelly-Borges M, Lobkovsky E, Clardy J: Dysidiolide: a novel protein phosphatase inhibitor from the Caribbean sponge dysidea etheria de laubenfels. J Am Chem Soc 1996, 118: 8759–8760. 10.1021/ja961961+View ArticleGoogle Scholar
- Avcibasi H, Anil H: Four terpenoids from Cedrus libanotica. Phytochemistry 1987, 26: 2852–2854. 10.1016/S0031-9422(00)83605-5View ArticleGoogle Scholar
- Miles DH, Chittawong V, Lho D-S, Payne AM, de La Cruz AA, Gomez ED, Weeks JA, Atwood JL: Novel sesquiterpene lactones from the mangrove plant Heritiera littoralis. J Nat Prod 1991, 54: 286–289. 10.1021/np50073a036View ArticleGoogle Scholar
- Marcos IS, Escola MA, Moro RF, Basabe P, Diez D, Sanz F, Mollinedo F, de la Iglesia-Vicente J, Sierrac BG, Urones JG: Synthesis of novel antitumour alanalogues of dysidiolide from ent-halimicacid. Bioorg Med Chem 2007, 15: 5719–5737. 10.1016/j.bmc.2007.06.007View ArticleGoogle Scholar
- Takahashi M, Dodo K, Sugimoto Y, Aoyagi Y, Yamada Y, Hashimoto Y, Shirai R: Synthesis of the novel analogues of dysidiolide and their structure–activity relationship. Bioorg Med Chem Lett 2000, 10: 2571–2574. 10.1016/S0960-894X(00)00527-8View ArticleGoogle Scholar
- Brohm D, Philippe N, Metzger S, Bhargava A, Muller O, Lieb F, Waldmann H: Solid-phase synthesis of dysidiolide-derived protein phosphatase inhibitors. J Am Chem Soc 2002, 124: 13171–13178. 10.1021/ja027609fView ArticleGoogle Scholar
- Wei M, Feng L, Li X, Zhou X, Shao Z: Synthesis of new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing gamma-butenolide moiety and preliminary evaluation of in vitro anticancer activity. Eur J Med Chem 2009, 44: 3340–3344. 10.1016/j.ejmech.2009.03.023View ArticleGoogle Scholar
- van Oeveren A, Jansen JFGA, Feringa BL: Enantioselective synthesis of natural dibenzylbutyrolactone lignans (−)-Enterolactone, (−)-Hinokinin, (−)-Pluviatolide, (−)-Enterodiol, and Furofuran Lignan (−)-Eudesmin via tandem conjugate addition to gamma-alkoxybutenolides. J Org Chem 1994, 59: 5999–6007. 10.1021/jo00099a033View ArticleGoogle Scholar
- Chen Q, Geng Z, Huang B: Synthesis of enantiomerically pure 5-(l-menthyloxy)-3,4-dibromo-2(5 H)-furanone and its tandem asymmetric Michael addition–elimination reaction. Tetrahedron Asymmetry 1995, 6: 401–404. 10.1016/0957-4166(95)00024-JView ArticleGoogle Scholar
- Smicius R, Burbuliene MM, Jakubkiene V, Udrwėnaitė E, Vainilavičius P: Convenient way to 5-substituted 4-amino-2,3-dihydro-4H-1,2,4-triazole-3-thiones. J Heterocyclic Chem 2007, 44: 279–284. 10.1002/jhet.5570440201View ArticleGoogle Scholar
- Reid JR, Heindel ND: Improved synthesis of 5-substituted −4-amino-3-mercapto-4H-1,2,4-triazoles. J Heterocyclic Chem 1976, 13: 925–926. 10.1002/jhet.5570130450View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.