Synthesis and In Vitro Cytotoxic Activity of Novel Chalcone-Like Agents

Document Type : Original Article


1 Department of Chemistry, Central Tehran-Branch, Islamic Azad University, Tehran, Iran

2 Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

3 Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

4 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran

5 Institute of Biochemistry and Biophysics, University of Tehran, Tehran, IranDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran

6 Department of Chemistry, Tabriz Branch, Islamic Azad University, Tabriz, Iran



Chalcones and their rigid analogues represent an important class of small molecules having anticancer activities. Therefore, in this study the synthesis and cytotoxic activity of new 3-benzylidenchroman-4-ones were described as rigid chalcone analogues.
Materials and Methods:
The reaction of resorcinol with 3-chloropropionic acid in the presence of CF3SO3H was afforded corresponding propiophenone. It was cyclized using 2M NaOH to give 7-hydroxy-4-chromanone. O-Alkylation of 7-hydroxy-4-chromanone with alkyl iodide in the presence of K2CO3 gave 7-alkoxychroman-4-one. Finally, condensation of chroman-4-one derivatives with different aldehydes afforded target compounds in good yields. The newly synthesized compounds were tested in vitro against different human cancer cell lines including K562 (human erythroleukemia), MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cells. The cell viability was evaluated using MTT colorimetric assay.
Most of the compounds showed good inhibitory activity against cancer cells. Among them, compound 4a containing 7-hydroxy group on chromanone ring and 3-bromo-4-hydroxy-5-methoxy substitution pattern on benzylidene moiety was the most potent compound with IC50 values ≤ 3.86 μg/ml. It was 6-17 times more potent than etoposide against tested cell lines.
We described synthesis and cytotoxic activity of poly-functionalized 3-benzylidenechroman-4-ones as new chalcone-like agents. These compounds can be considered as conformationally constrained congeners of chalcones to tolerate the poly-functionalization on the core structures for further optimization.


1. Harrison M, Holen K, Liu G. Beyond taxanes: a review of novel agents that target mitotic tubulin and microtubules, kinases, and kinesins. Clin Adv Hematol Oncol 2009; 7:54–64.
2. Eckhardt S: Recent progress in the development of anticancer agents. Curr Med Chem-Anti-Cancer Agents 2002; 2:419–439.
3. Sierra JR, Cepero V, Giordano S. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Mol Cancer 2010; 9:75–88.
4. Hinnen P, Eskens FA. Vascular disrupting agents in clinical development. Br J Cancer 2007; 96:1159–1165.
5. Dimmock JR, Elias DW, Beazely MA, Kandepu NM. Bioactivities of chalcones. Curr Med Chem 1999; 6:1125–1149.
6. Shi H-B, Zhang S-J, Ge Q-F, Guo D-W, Cai C-M, Hu W-X. Synthesis and anticancer evaluation of thiazolyl–chalcones. Bioorg Med Chem Lett 2010; 20:6555–6559.
7. Firoozpour L, Edraki N, Nakhjiri M, Emami S, Safavi M, Ardestani SK,
et al. Cytotoxic activity evaluation and QSAR study of chromene-based chalcones. Arch Pharm Res 2012; 35:2117-2125.
8. Go ML
, Wu X, Liu X. Chalcones: An update on cytotoxic and chemoprotective properties. Curr Med Chem 2005; 12:483499.
9. Aryapour H, Riazi GH, Foroumadi A, Ahmadian S, Shafiee A, Karima O,
et al. Biological evaluation of synthetic analogues of curcumin: chloro-substituted-2'-hydroxychalcones as potential inhibitors of tubulin polimerization and cell proliferation. Med Chem Res 2011; 20:503–510.
10. Shan Y
, Zhang J, Z Liu, M Wang, Dong Y. Developments of combretastatin A-4 derivatives as anticancer agents. Curr Med Chem 2011; 18:523538.
11. Dimmock JR
, Kandepu NM, Zanarali AJ, Kowalchuk TP, Motagabahalli N, Quail JW, et al. Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones. J Med Chem 1999; 42:13581366. Cytotoxic Activity of Novel Chalcone-like agents Letafat et al
Iran J Basic Med Sci, Vol. 16, No. 11, Nov 2013
12. Dimmock JR
, Zello GA, Oloo EO, Quail JW, Kraatz H-B, Perjési P, et al. Correlations between cytotoxicity and topography of some 2-arylidenebenzocycloalkanones determined by X-ray crystallography. J Med Chem 2002; 45:31033111.
13. Perjési P
, Das U, De Clercq E, Balzarini J, Kawase M, Sakagami H, et al. Design, synthesis and antiproliferative activity of some 3-benzylidene-2,3-dihydro-1-benzopyran-4-ones which display selective toxicity for malignant cells. Eur J Med Chem 2008; 43:839845.
14. Rafinejad A, Fallah-Tafti A, Tiwari R, Nasrolahi Shirazi A, Mandal D, Shafiee A,
et al. 4-Aryl-4H-naphthopyrans derivatives: One-pot synthesis, evaluation of Src kinase inhibitory and anti-proliferative activities. Daru J Pharm Sci 2012; 20:100.
15. Bazl R, Ganjali M, Saboury A, Foroumadi A, Nourozi P, Amanlou M. A new strategy based on pharmacophore-based virtual screening in adenosine deaminase inhibitors detection and
in vitro study. Daru J Pharm Sci 2012; 20:64.
16. Vosooghi M, Divsalar K, Shamsa H, Kheirollahi A, Safavi M, Ardestani SK,
et al. Synthesis and in vitro cytotoxic activity evaluation of 16-(substituted benzylidene) derivatives of dehydroepiandrosterone. Daru J Pharm Sci 2013; 21:34.
17. Foroumadi A, Samzadeh-Kermani A, Emami S, Dehghan GH, Sorkhi M, Arabsorkhi F,
et al. Synthesis and antioxidant properties of substituted 3-benzylidene-7-alkoxychroman-4-ones. Bioorg Med Chem Lett 2007; 17:6764–6769.
18. a) Nakhjiri M, Safavi M, Alipour E, Emami S, Atash AF, Jafari-Zavareh M,
et al. Asymmetrical 2,6-bis(benzylidene)cyclohexanones: Synthesis, cytotoxic activity and QSAR study. Eur J Med Chem 2012; 50:113–123. b) Safavi M, Esmati N, Ardestani SK, Emami S, Ajdari S, Davoodi J, et al. Halogenated flavanones as potential apoptosis-inducing agents: synthesis and biological activity evaluation. Eur J Med Chem 2012; 58:573-580.
19. Noushini S, Emami S, Safavi M, Kabudanian Ardestani S, Gohari AR, Shafiee A,
et al. Synthesis and cytotoxic properties of novel (E)-3-benzylidene-7-methoxychroman-4-one derivatives. Daru J Pharm Sci 2013; 21:31.
20. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65:55–63.