Design, Synthesis, and Biological Evaluation of Benzimidazole-Derived Biocompatible Copper(II) and Zinc(II) Complexes as Anticancer Chemotherapeutics.

Mohamed Alajmi,Perwez Shaikh,Azmat Khan,Md Rehman,Rais Khan,Afzal Hussain

doi:10.3390/ijms19051492

Mohamed Alajmi, Perwez Shaikh + Show 4 more

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https://doi.org/10.3390/ijms19051492

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Abstract

Herein, we have synthesized and characterized a new benzimidazole-derived “BnI” ligand and its copper(II) complex, [Cu(BnI)2], 1, and zinc(II) complex, [Zn(BnI)2], 2, using elemental analysis and various spectroscopic techniques. Interaction of complexes 1 and 2 with the biomolecules viz. HSA (human serum albumin) and DNA were studied using absorption titration, fluorescence techniques, and in silico molecular docking studies. The results exhibited the significant binding propensity of both complexes 1 and 2, but complex 1 showed more avid binding to HSA and DNA. Also, the nuclease activity of 1 and 2 was analyzed for pBR322 DNA, and the results obtained confirmed the potential of the complexes to cleave DNA. Moreover, the mechanistic pathway was studied in the presence of various radical scavengers, which revealed that ROS (reactive oxygen species) are responsible for the nuclease activity in complex 1, whereas in complex 2, the possibility of hydrolytic cleavage also exists. Furthermore, the cytotoxicity of the ligand and complexes 1 and 2 were studied on a panel of five different human cancer cells, namely: HepG2, SK-MEL-1, HT018, HeLa, and MDA-MB 231, and compared with the standard drug, cisplatin. The results are quite promising against MDA-MB 231 (breast cancer cell line of 1), with an IC50 value that is nearly the same as the standard drug. Apoptosis was induced by complex 1 on MDA-MB 231 cells predominantly as studied by flow cytometry (FACS). The adhesion and migration of cancer cells were also examined upon treatment of complexes 1 and 2. Furthermore, the in vivo chronic toxicity profile of complexes 1 and 2 was also studied on all of the major organs of the mice, and found them to be less toxic. Thus, the results warrant further investigations of complex 1.

Highlights

The serendipitous discovery of cisplatin [1] as an anticancer chemotherapeutic agent [2,3,4] swiftly marked significant breakthroughs in the field of metallodrugs as potential anticancer agents [5], and prompted several researchers and groups to explore the field of the metal-based chemotherapeutic [6]
Zinc ion is needed; it regulates the metabolism of the cells and is a major regulatory ion in the metabolism of cells, which shrink the cardiotoxicity and hepatotoxicity that is associated with several anticancer drugs [13,14]
The yellow precipitate was isolated via rotavapor and recrystallized in methanol as a yellow-crystalline material suitable for X-ray crystallography

Summary

Introduction

The serendipitous discovery of cisplatin [1] as an anticancer chemotherapeutic agent [2,3,4] swiftly marked significant breakthroughs in the field of metallodrugs as potential anticancer agents [5], and prompted several researchers and groups to explore the field of the metal-based chemotherapeutic [6]. Several potential metallodrugs were discovered since and were used in clinics worldwide to treat cancers, starting from cisplatin, oxaliplatin, carboplatin, etc. The severe side effects and resistance by the cancer cells confine their clinical application widely [7]. NAMI-A “(imidazole)RuCl4(DMSO)(imidazole)” and KP1019 “(indazole)RuCl4(DMSO)(indazole)” as ruthenium-centered potential anticancer drugs entered into the clinical trials, but still lead to side effects, and cost remains a hurdle. Many scientists concentrated their attention on transition metals, copper and zinc, to design novel metal-based anticancer agents. Both the metal ions are bio-essential elements that play a prominent role in the active site of many metalloproteins. Zinc ion is needed; it regulates the metabolism of the cells and is a major regulatory ion in the metabolism of cells, which shrink the cardiotoxicity and hepatotoxicity that is associated with several anticancer drugs [13,14]

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