Synthesis, DNA binding, cellular DNA lesion and cytotoxicity of a series of new benzimidazole-based Schiff base copper(II) complexes

• Published in: Dalton transactions : an international journal of inorganic chemistry 2015-01, Vol.44 (46), p.19983-19996
• Main Authors: Paul, Anup, Anbu, Sellamuthu, Sharma, Gunjan, Kuznetsov, Maxim L, Koch, Biplob, Guedes da Silva, M Fátima C, Pombeiro, Armando J L
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferatives; Apoptosis - drug effects; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Binding; Cancer; Cattle; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper - chemistry; Copper - pharmacology; Crystallography, X-Ray; Deoxyribonucleic acid; DNA - chemistry; DNA - metabolism; Fluorescence; HeLa Cells; Humans; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Mathematical analysis; Models, Molecular; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Schiff bases; Schiff Bases - chemistry; Schiff Bases - pharmacology
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c5dt02880a

A series of new benzimidazole containing compounds 2-((1-R-1-H-benzimidazol-2-yl)phenyl-imino)naphthol HL(1-3) (R = methyl, ethyl or propyl, respectively) have been synthesized by Schiff base condensation of 2-(1-R-1-H-benzo[d]imidazol-2-yl)aniline and 2-hydroxy-1-naphthaldehyde. The reactions of HL(1-3) with Cu(NO3)2·2.5H2O led to the corresponding copper(II) complexes [Cu(L)(NO3)] 1-3. All the compounds were characterized by conventional analytical techniques and, for 1 and 3, also by single-crystal X-ray analysis. The interactions of complexes 1-3 with calf thymus DNA were studied by absorption and fluorescence spectroscopic techniques and the calculated binding constants (K(b)) are in the range of 3.5 × 10(5) M(-1)-3.2 × 10(5) M(-1). Complexes 1-3 effectively bind DNA through an intercalative mode, as proved by molecular docking studies. The binding affinity of the complexes decreases with the size increase of the N-alkyl substituent, in the order of 1 > 2 > 3, which is also in accord with the calculated LUMO(complex) energies. They show substantial in vitro cytotoxic effect against human lung (A-549), breast (MDA-MB-231) and cervical (HeLa) cancer cell lines. Complex 1 exhibits a significant inhibitory effect on the proliferation of the A-549 cancer cells. The antiproliferative efficacy of 1 has also been analysed by a DNA fragmentation assay, fluorescence activated cell sorting (FACS) and nuclear morphology using a fluorescence microscope. The possible mode for the apoptosis pathway of 1 has also been evaluated by a reactive oxygen species (ROS) generation study.