Molecular Design, Synthesis and Biological Evaluation of Novel Transition Metal Complexes Featuring ON, ONO & ONS Donor Ligands

Abstract

Development of novel transition metal based compounds for their potential applications as therapeutic or diagnostic agents is an integral part of medicinal chemistry. Transition metal complexes have been widely used as chemotherapeutic agents in the treatment of several types of malignancies, such as colon, lung and breast cancers. Moreover, they can exist in a variety of oxidation states and this characteristic enable them to accommodate a variety of organic molecules or ligands around them. Designing of new ligands through judicious substitution and tuning of metal-binding sites offers the opportunity in the modification and advancement of such agents, thus making metal based drugs promising pharmacological candidates. A number of reports of metal complexes encourage further studies for exploration of new metallodrugs with attractive properties like biological potency, easy accessibility, least toxicity and improved physical profile. Bearing these factors in mind, in this dissertation the chemistry of a series of transition metal (V, Ni, Mo, Cu, Ru, & Zn) complexes of tri- and tetradentate ONO, ONS and ONNO donating azohydrazones, aroylhydrazone, thiosemicarbazones and salan ligands are reported, with special reference to their pharmacological activity and solution property. All the synthesized ligands and their corresponding metal complexes have been successfully characterized by several physicochemical (elemental analysis), spectroscopic (UV-Vis, IR and NMR), spectrometric (ESI-MS) and electrochemical (cyclic voltammetry) methods. The structures of the complexes were further confirmed by single crystal X-ray diffraction analysis. The solution behavior of few complexes has also been studied in order to understand their transformation, interconversion, changes in coordination geometry, and nuclearity taking place in solution phase. Therein, the complexes were studied for their biological activity through interaction with DNA (Calf Thymus DNA, G-quadruplex DNA and Supercoiled pUC19 DNA) and proteins (Human Serum Albumin) through various analytical and electrophoresis techniques. The in vitro antiproliferative activity of the synthesized complexes was studied against different cancer [human cervical cancer (HeLa), human colorectal adenocarcinoma (HT-29), human breast adenocarcinoma, (MCF-7)], and noncancerous cell lines [human epidermal keratinocyte cells (HaCaT) and mouse embryonic fibroblast cell line (NIH-3T3)]. Additionally, the zinc complexes were evaluated for their phosphatase activity by using para-nitrophenyl phosphate (PNPP) and bis(2,4–dinitrophenyl)phosphate (BNPP) as substrates. The results obtained from the above studies suggested the test complexes to be excellent DNA and protein binders. In addition, the in vitro antiproliferative activity of the complexes points toward their significance as potential lead molecules for drug designing. The complexes studied herein showed similar, or in some cases even better in vitro cytotoxicity on comparison to various clinically reported chemotherapeutic drugs. Besides, the zinc complexes showed moderate phosphatase activity against model substrates. Finally, a plausible rationale for the enhanced biological activities of all the complexes like results of modifications in the ligand environment and the nature or the number of metal centers has also been discussed Apart from that, the catalytic applications (especially in oxidative bromination of thymol and styrene) of vanadium(V) complexes and magnetic susceptibility of dimeric copper(II) complexes has also been explored keeping their individual metal importance in consideration.