Chemistry of Vanadium(IV/V) and Ruthenium(II) Complexes with O- and/or N- and/or S- Donor Ligands Incorporating Bio-Active Molecules in Relation to their Anticancer Activity

Abstract

The history of transition metal complexes in anticancer research is a fascinating journey that in progress for the last several decades. In the 1960s, with the discovery of cisplatin as a potential anticancer drug, the investigation of non-platinum-based transition metal complexes marked the beginning of the field's exploration of cancer therapy. Transition metal complexes have significant attention due to their potential to serve as innovative and effective agents in the treatment of cancer. In addition, the adaptability in oxidation states allows the transition metals to form various coordination complexes with different types of organic ligands or molecules and exhibit different chemical and biological behaviors. Thus, designing new ligands through thoughtful substitution and tuning of metal-binding sites could be a great area of research on advancement of the metal-based compounds as promising anticancer drugs. Several reports of metal complexes encourage further studies for the exploration of new metallodrugs with attractive properties like biological potency, easy accessibility, least toxicity, and improved physical profile. However, few transition metal complexes already have progressed into human and clinical testing. Keeping these factors in mind, in this dissertation the chemistry of vanadium(IV/V) and ruthenium(II)-based transition metal complexes with O- and/or N- and/or S- donating Schiff base, aroylhydrazones, and dithocarbazates ligands are described, with special addressing to their aqueous/solution behavior and pharmacological activity. All the synthesized ligands and their respective metal complexes have been successfully characterized by elemental analysis, spectroscopic (UV-vis, IR, and NMR), spectrometric (HR‒ESI‒MS), and electrochemical methods. The structures of the complexes were further confirmed by single- crystal X-ray diffraction analysis. The solution behavior of all the complexes has been studied in order to understand their stability, transformation, interconversion, changes in coordination geometry, and nuclearity taking place in the aqueous/cell culture medium. Further, the biomolecular interactions of the investigated complexes were studied with DNA (Calf thymus DNA, CT‒DNA) and proteins (Bovine serum albumin, BSA) through various analytical techniques (absorption, fluorescence, and circular dichroism studies). The in vitro anticancer activity of the synthesized complexes was studied against different cancerous cell lines such as human cervical cancer (HeLa), human breast adenocarcinoma, (MCF-7), human colorectal adenocarcinoma (HT-29), human lung adenocarcinoma (A549) and noncancerous cell lines mouse embryonic fibroblast cell line (NIH-3T3)]. Results of the aforementioned experiments showed that the tested complexes bind DNA and proteins more effectively. Furthermore, the in vitro anticancer activity of the complexes implies that they are potentially useful as lead compounds for drug development. Further interest in the investigation of the mechanism of action of these metallodrugs for which various experiments were conducted such as apoptosis analysis, reactive oxygen species (ROS) generation, mitochondria membrane potential (MMP), etc. by live cell confocal microscopy and flow cytometer techniques. Apart from that, as few compounds of the series are found fluorescence active, their intracellular colocalization studies were performed and resulted in targeting the mitochondria of the cell.