Synthesis and cytotoxic activities of novel phenacylimidazolium bromides Xiao-Dong Yang a,  , Xiang-Hui Zeng a,  , Yan-Li Zhang b , Chen Qing b, * , Wen-Jian Song a , Liang Li a , Hong-Bin Zhang a, * a Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China b Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650031, PR China article info Article history: Received 5 January 2009 Revised 11 February 2009 Accepted 16 February 2009 Available online 21 February 2009 Keywords: Phenacylimidazolium bromides Synthesis Cytotoxic activities Structure–activity relationships abstract A series of novel phenacylimidazolium derivatives, bearing an aryl or alkyl substituent at position-1 and a phenacyl substituent at position-3 of the imidazole ring, has been prepared and evaluated in vitro against a panel of human tumor cell lines. Phenacylimidazolium bromides bearing a highly sterically hindered aryl group at position-1 and an electron-rich phenacyl or naphthylacyl substituent at position-3 of imid- azole ring proved to be more active than imidazolium bromides with other substituted groups. In partic- ular, compound 5j was found to be the most potent compounds with IC 50 values lower than 5.0 lM against 8 strains human tumor cell lines and more active than cisplatin (DDP). Ó 2009 Elsevier Ltd. All rights reserved. Imidazolium salts have attracted considerable interests in re- cent years for their versatile properties in chemistry and pharma- cology. They are well-known as room-temperature ionic liquids that can be used as electrolytes or green solvents because of their low vapor pressure and wide chemical stability. 1 Imidazolium salts are also used as precursors for stable carbenes with many applica- tions in organic synthesis. 2,3 A number of biological activities of imidazolium salts have been reported including antimicrobial and antifungal (l,3-dialky imidazo- lium chlorides), 4 antitumor (l,3-dialky imidazolium iodides), 5 antimuscarinic (1,3-disubstituted imidazolium halides), 6 throm- boxane synthetase inhibition (1,3-disubstituted imidazolium ha- lides), 7 anti-inflammatory (enol betaines of phenacyl halides), 8 antiarrhythmic (1,3-disubstituted imidazolium halides), 9 and plas- mid DNA cleavage (monometallic cyclen complexes containing 1,3-disubstituted imidazolium bromides group) 10 activity. In 1989, a series of phenacylimidazolium halides were synthesized and found to possess effective hypoglycemic activity by Dominianni. 11 Progly- cosyn (LY177507, 1, Fig. 1), a representative of these compounds, stimulates glycogen synthesis and inhibits glucose production from various substrates in rat hepatocytes. 12 Additionally, phenacylimi- dazolium salts have been used as intermediates in a regiospecific synthesis of 3-substituted L-histidines. 13 To the best of our knowl- edge, however, no reports concerning antitumor activity for phena- cylimidazolium salt was reported. The present investigation was stimulated by the discovery of two new imidazolium halides (Fig. 1), 1,3-dibenzyl-4,5-dimethy- limidazolium chloride (2) and 1,3-dibenzyl-2,4,5-trimethylimi- dazolium chloride (3), isolated from the roots of Lepidium meyenii, which showed potent cytotoxic activity against the hu- man cancer cell lines (UMUC3, PACA2, MDA231, and FDIGROV). 14 In our efforts to discover effective ligands for catalytic organic transformation and active agents toward antitumor activity, we were particularly interested in the imidazole ring. Our long stand- ing interest in imidazole has resulted in the synthesis of a number of imidazolium salts. 15 In the present research, we have designed and synthesized a series of novel imidazolium bromides, bearing an aryl or alkyl substituent at position-1 and a phenacyl substitu- ent at position-3 of imidazole ring. The purpose of this study was to investigate effect of phenacylimidazolium bromides on the anti- tumor activity, with the ultimate aim of developing novel potent antitumor agents. Based on the synthetic method described in our previous reports, 16,17 a number of 1-aryl and 1-alkyl substituted imidazoles 4a–4u were prepared, including a few N-arylimidazoles and N-alkylimidazoles with highly electron-rich and highly sterically hindered substituted groups (method A and B, Scheme 1). 18 Twenty-one phenacylimidazolium salts were prepared as shown in Scheme 1. 1-Aryl/alkyl and 3-phenacyl substituted imidazolium bromides (compounds 5a–5u) were prepared with highly yields by reaction of 1-aryl or 1-alkyl substituted imidazoles with the 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.02.065 * Corresponding authors. Tel.: +86 871 5031119; fax: +86 871 5035538 (H.-B.Z.). E-mail addresses: zhanghbyd@gmail.com, zhanghb@yun.edu.cn (H.-B. Zhang).   These authors contributed equally to this paper. Bioorganic & Medicinal Chemistry Letters 19 (2009) 1892–1895 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl