Studies On Synthesis And Anticancer Activity Of Benzimidazole-Quinoline Metal Complexes

The research of cisplatin as anticancer activity provides a great impetus for the development of new metal complexes as anticancer drugs.Cisplatin and its derivatives have been used successfully in multiple cancer treatments.Unfortunately,adverse side effects,including renal toxicity,ototoxicity,peripheral neuropathy,and drug resistance in cancer cells as well as the problems of poor solubility and/or permeability limits their applications,which leads to the development of other metal complexes with low toxicity and prominent solubility as well as better anticancer activity.Based on this,seven metal complexes containing benzimidazoline-quinoline ligands were synthesized and characterized in this paper,and the antitumor activity of the complexes was studied.1.Complexes[Cu?pbmq?Cl₂]₂?1?,[Cu?pbmq?Br₂]₂?2?and[Pt?pbmq?Cl₂]?3?derived from 2-??2-?pyridin-2-yl?-1H-benzo[d]imidazol-1-yl?methyl?quinolone?pbmq?have been prepared and characterized.These complexs showed much higher cytotoxicity than pbmq against the tested cancer cell lines.Notably,complex 1exhibited marked anticancer activity against SMMC7721 cells,with IC₅₀values of4.28±0.33?M.Hence,complex 1 was selected for further studies to understand the underlying mechanisms of its anticancer activity.Fluorescence,CD spectroscopy studies and viscosity determination showed that complex 1 could strongly bind to calf thymus DNA?CT-DNA?.The CT-DNA binding properties revealed that intercalation might be the most probable binding mode.Moreover,complex 1 exhibited DNA cleavage activity.Cell uptake implied that complex 1 could enter the cells and accumulate mainly in the nucleus.Besides,flow cytometry analysis indicated that complex 1 could induce cycle arrest in G2-M phase and apoptosis in SMMC7721cells.Further experiments confirmed that complex 1 triggered apoptosis in SMMC7721 cells via the intrinsic mitochondrial pathway.2.Using hydrophobic triphenylphosphine?TPP?ligand results in complexes with good cytotoxicity,as its introduction is regarded as an effective approach to increase uptake property of the complexes.Complexes[Cu?2-pbmq??CH₃OH?Br₂]?4?,[Cu?2-pbmq??CH₃OH?Cl₂]?5?,[Cu?2-pbmq??TPP?Br]₂?6?and[Cu?2-pbmq??TPP?I]₂?7?,based on 2-??2-?pyrazin-2-yl?-1H-benzo[d]imidazole-1-yl?methyl?)quinolone?2-pbmq?,have been designed,synthesized and characterized by X-ray crystallography to investigate the influence of triphenylphosphine group on the anticancer activity.Though,the DNA interaction property of complex was slightly decreased,the in vitro antiproliferative activity and cellular uptake of complex in the presence of triphenylphosphine were markedly increment.Furthermore,the anticancer properties of complex 6 introducing triphenylphosphine group were investigated,revealing that complex 6 acculumated in nucleus,arrested cell cycle in G0-G1 phase,causing mitochondrial dysfunction involving simultaneous mitochondrial membrane potential collapse,ATP depletion and Ca²⁺leakage,and eventually inducing cellular apoptosis.As a result,the introduction of triphenylphosphine group excellently influences the biological activityand cytotoxicity of the complexes.