SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW TITANIUM(IV) COMPLEXES AND THEIR USE IN ANTI-CANCER TREATMENT

Abstract

This thesis considers the synthesis, and characterisation of new fulvene ligands and titanium(IV) complexes and evaluation of their potential as anti-cancer agents. It contains the in vitro cell results from different techniques used to investigate their biological mechanisms of action and their activity against human cancer cell lines. Chapter One covers an introduction to the PhD project, including a literature search focusing on previously synthesised titanium anti-cancer compounds (1979-2020), and a description of the aims of the thesis. Chapter Two discusses the synthesis and characterisation of novel (R)-3- (cyclopenta-2,4-dien-1-ylidene)-2,3-dihydro-1H-inden-1-ol ligand precursors (two X-ray structures reported) attained via iminium-based organo catalysis in 53-78% yield (> 99% er). Unsuccessful attempts to form new titanocene complexes from these ligands are also discussed. Chapter Three discusses the synthesis and characterisation of novel titanium(IV) complexes, using [ONO] donor atom sets from underutilised 2,2’-((methylazanedyl) bis(methylene)diphenol ligands. Complexes featuring different substituents (e.g. Cl, Me, OMe) ortho and para to the phenolic donors can be prepared in good yield (66- 89%, eight examples). The structures of these complexes were proved by X-ray crystallography in four cases and studies of their hydrolysis in DMSO/water mixtures have conducted by 1H NMR spectroscopy and LCMS. In one case a [(ONO ligand)Ti (OH)(OH2)]+ intermediate can be detected. Biological studies, including MTT and clonogenic techniques, show high anti-cancer activity for these species (GI50 values down to 1 µM for the MCF-7 cell line). The mode of action of these agents was studied by annexine-V, cell cycle analysis, γ-H2AX, and caspase Abstract II techniques. The antiproliferative activity of the new [ONO] donor atom titanium complexes compares favourably or outperforms cisplatin, in five carcinoma cell lines: HCT-116 (colorectal cancer) MCF-7 (breast cancer), MDA-MB-468 (breast cancer), PANC-1 (pancreatic cancer), and HT-29 (colon cancer). Thus, the new [ONO] donor atom complexes developed herein are some of the most active anti cancer titanium species presently known. Chapter Four presents the experimental details and characterisation data for all compounds described in Chapters Two and Three. It also provides protocols for all biological studies.