Haque Rosenani A, Iqbal Muhammad Adnan, Khadeer Ahamed Mohamed B, Majid Ams Abdul, Abdul Hameed Zena A
School of Chemical Sciences, Universiti Sains Malaysia, USM-11800, Penang, Malaysia.
Chem Cent J. 2012 Jul 18;6(1):68. doi: 10.1186/1752-153X-6-68.
Benzimidazole derivatives are structurally bioisosteres of naturally occurring nucleotides, which makes them compatible with biopolymers of living systems. This property gives benzimidazole a biological and clinical importance. In the last decade, this class of compounds has been reported to possess anti-allergic, anti-diabatic, anti-HIV, anti-hypertensive, anti-inflammatory, anti-mycobacterial, anti-oxidant, anti-protozoal, and anti-viral properties. The researchers are now interested to explore their potential as anti-cancer agents. In the present study, an effort was made to further explore this area of research. Furthermore, in order to increase the solubility and efficacy of these heterocycles, the interest is now shifted to the salts of these compounds. With this background, we planned to synthesize a series of meta-xylyl linked bis-benzimidazolium salts to assess their anti-proliferation efficacy on human colon cancer cell line (HCT 116).
A number of N-alkylbenzimidazoles were synthesized by reactions of benzimidazole with alkyl halides (i-PrBr, PrBr, EthBr, Pent-2-ylBr, BuBr, BenzCl, HeptBr). The subsequent treatment of the resulting N-alkylbenzimidazoles with 1,3-(bromomethylene)benzene afforded corresponding bis-benzimidazolium salts. All synthesized compounds were characterized by spectroscopic techniques (Additional file 1: NMR & FT-IR) and microanalysis. Molecular structures of selected compounds were established through single crystal x-ray diffraction studies. All the compounds were assessed for their anti-proliferation test on human colorectal cancer cell line (HCT 116). Results showed that the compounds exhibited dose dependent cytotoxicity towards the colon cancer cells with IC50 ranges between 0.1 to 17.6 μM. The anti-proliferation activity of all compounds was more pronounced than that of standard reference drug 5-flourouracil (IC50 =19.2 μM).
All the synthesized bis-benzimidazolium salts showed potential anticancer activity. Out of them, some of these salts showed IC50 value as low as 0.1-0.2 μM. Based on the results it can be concluded that, the bis-benzimidazolium salts could probably be the potential source of chemotherapeutic drugs.
苯并咪唑衍生物是天然存在核苷酸的结构生物电子等排体，这使其能够与生命系统的生物聚合物相容。这一特性赋予了苯并咪唑生物学和临床重要性。在过去十年中，据报道这类化合物具有抗过敏、抗糖尿病、抗艾滋病毒、抗高血压、抗炎、抗分枝杆菌、抗氧化、抗原虫和抗病毒特性。研究人员现在有兴趣探索它们作为抗癌剂的潜力。在本研究中，我们努力进一步探索这一研究领域。此外，为了提高这些杂环化合物的溶解度和功效，现在人们的兴趣转向了这些化合物的盐。在此背景下，我们计划合成一系列间二甲苯基连接的双苯并咪唑鎓盐，以评估它们对人结肠癌细胞系（HCT 116）的抗增殖功效。
通过苯并咪唑与卤代烷（异丙基溴、丙基溴、乙基溴、2-戊基溴、丁基溴、苄基氯、庚基溴）反应合成了多种N-烷基苯并咪唑。随后将所得的N-烷基苯并咪唑与1,3-（溴亚甲基）苯处理，得到相应的双苯并咪唑鎓盐。所有合成的化合物均通过光谱技术（补充文件1：核磁共振和傅里叶变换红外光谱）和微量分析进行了表征。通过单晶X射线衍射研究确定了所选化合物的分子结构。对所有化合物进行了对人结肠癌细胞系（HCT 116）的抗增殖测试。结果表明，这些化合物对结肠癌细胞表现出剂量依赖性细胞毒性，IC50范围在0.1至17.6 μM之间。所有化合物的抗增殖活性均比标准参考药物5-氟尿嘧啶（IC50 = 19.2 μM）更为显著。
所有合成的双苯并咪唑鎓盐均显示出潜在的抗癌活性。其中一些盐的IC50值低至0.1 - 0.2 μM。基于这些结果可以得出结论，双苯并咪唑鎓盐可能是化疗药物的潜在来源。
