Self-Assembly and Cytotoxic Activity of Homometallic and Heterometallic Coordination Architectures
Adeyemo, Aderonke Ajibola
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The alluring order in which complex biological networks exist in nature stimulated the interest of chemists to replicate such systems synthetically. With such examples as the deoxyribonucleic acid (DNA) double helix and the phospholipid bilayers, the influence of forces within these networks are solely credited for their excellent stability. The synthetically ordered chemical networks are also held together by interactions within them with little or no external force as seen in the natural systems. This spontaneous and reversible association of molecules or ions to form larger, more complex entities according to the intrinsic information contained in the molecules themselves is known as self-assembly. The self-assembly process is pre-eminent to the formation of ordered structures emerging spontaneously from the precursors in which, the overall structure of the final assemblies is controlled by the symmetry of each of the building blocks. The highly ordered and thermodynamically stable scaffolds are formed via non-covalent interactions including hydrophobic interaction, π-stacking, dipole-dipole interaction, ion-dipole interaction, hydrogen bonding, Van der Waals forces, solvophobic interaction and reversible metal-ligand coordination. These non-covalent interactions are termed as supramolecular interactions. Among several of these self-assembly protocols, the directional metal-ligand coordination strategy has evolved to be a well-established process for the preparation of supramolecular ensembles with pre-defined shapes, cavities and functionalities in a “one-pot” synthesis. Coordination-driven self-assembly strategy is governed by the combination of electron-deficient metal centres and electron-rich organic ligands. The outcome of the final supramolecular architecture is determined by the choice of the pre-designed metal acceptor building blocks as well as the flexibility and steric demands of the ancillary organic ligands. Accurate stoichiometry of each of the building blocks is also a very important factor in coordination-driven self-assembly; although serendipity sometimes happen which is quite unexpected. A large number of these self-assembled supramolecular networks have found useful applications in optoelectronics, material chemistry, adsorption, drug delivery, catalysis, host-guest chemistry, photo- and electro-chemical sensing as well as prospective chemotherapeutics. Transition metals are widely desired as electron-deficient building blocks in supramolecular chemistry. They readily accept lone pair of electrons from electron-rich building blocks. The functional properties of these metals have also been considered during the pre-design of these electron acceptors such that the functional property of each metal can be induced in the final architecture. Pd(II) and Pt(II) metals are highly desirable electron acceptors in supramolecular self-assembly because of their rigid square-planar nature. Nonetheless, Ru(II) and Fe(II) have also been explored as electron acceptors based on their octahedral geometry. Electron-rich building blocks have lone pairs of electrons on their donor sites (nitrogen, oxygen or sulphur) which effortlessly donate electrons to electron-deficient building blocks. The pyridyl appended ligands have been mostly used as the electron-rich building blocks in the construction of supramolecular architectures because of their predictable coordination modes and the symmetrical nature. However, imidazole appended ligands holds a distinctive spot in supramolecular chemistry because of its rotational flexibility and unpredictable binding modes which may lead to uncommon architectures not obtainable with pyridyl appended ligands. Thus, imidazole-based supramolecular architectures are less explored because the outcome of the final architecture cannot be pre-determined during the design. Ruthenium p-cymene complexes have spurred much interest in the last two decades because they possess extremely stable octahedral geometry and has been extensively used in the construction of 2D and 3D supramolecular architectures. The recent search for viable alternatives to platinum drugs in cancer chemotherapy discovered ruthenium as an excellent alternative to platinum because of its low toxicity when compared to platinum. The robustness of the arene head on interaction with biomolecules and the accumulation of large molecular weight compounds specifically in cancer cells rather than in healthy cells also improved the activity of ruthenium supramolecular architectures in cancer therapy. This recent outcome has propelled significant research channelled towards synthesizing better ruthenium-based chemotherapeutics. Additionally, the presence of two different metals in a single self-assembled architecture may also impart an increased activity when compared to the individual activity of each metal. Thus, the heterometallic supramolecular architectures can open a new kind of chemotherapeutics which may give a distinct mechanistic pathway different from those reported in literature. Chapter 1 of this thesis describes the coordination-driven self-assembly strategy with specific emphasis on ruthenium p-cymene self-assembled architectures and their applications. A brief introduction on cancer and cancer therapy is discussed. The use of mononuclear and dinuclear metal-based chemotherapeutics is included while the use of heterometallic complexes as anticancer agents was also highlighted. Chapter 2 showcases the self-assembly of a series of 2D and 3D ruthenium(II) p-cymene architectures constructed from bidentate and tridentate rigid imidazole-based ligands and dinuclear ruthenium(II) building units. The influence of the rotational flexibility of the imidazole ligands on the final architecture was probed. In spite of the likelihood of the formation of different conformational isomeric architectures (syn and anti) and/or polymeric products due to free rotation on the donor sites of the imidazole ligands, the exclusive formation of a single conformational isomer (anti) as the only product turned out to be a noteworthy observation. This indicates that the coordination mode and flexibility of imidazole ligand can control and determine the geometry, topology and conformations of the final molecular architectures. Scheme 1: Self-assembly of 2D macrocycles [2 - 7](OTf)4 employing dinuclear ruthenium(II) building units [1a - 1c](OTf)2 and bidentate rigid imidazole ligands L1 - L2 in methanol at room temperature. Furthermore, the unexpected formation of a tetranuclear cationic macrocycle (OTf)4 was reported in the 2 + 3 self-assembly reaction of triazine-based tridentate imidazole ligand L3 and dinuclear ruthenium(II) building unit [1a](OTf)4 over the expected hexanuclear prismatic cage [8a](OTf)6 which is quite surprising. Scheme 2: Schematic representation of the formation of an unexpected tetranuclear macrocycle (OTf)4 over the expected hexanuclear prismatic cage [8a](OTf)6. Chapter 3 reports the synthesis of eight octanuclear cages via the coordination-driven self-assembly of two tetradentate pyridyl-based organic ligands and four dinuclear p-cymene Ru(II) acceptor clips. These octanuclear cages were explored in vitro as potential anticancer agents against human lung adenocarcinoma A549 and human cervical cancer HeLa cell lines. Four of the cages with polyaromatic spacers in their Ru(II) acceptor clip unit showed very low micromolar IC50 values and also possess higher anticancer activity than cisplatin against the tested cancer cell lines. The four dinuclear p-cymene Ru(II) acceptor clips A3 in OC-3 and OC-7 revealed some kind of synergy which is evident in their IC50 values against the tested cancer cell lines. In addition, OC-3 and OC-7 trigger both early and late apoptotic phases while OC-4 and OC-8 trigger majorly late apoptotic phase in the cancer cell lines tested. The mechanistic pathway by which cell death is progressing is through the generation of reactive oxygen species (ROS) which is of significant amount in OC-4 and OC-8. Scheme 3: Self-assembly of the discrete octanuclear cages (OC-1 - OC-8) in methanol at room temperature and the schematic illustration of the apoptosis mechanistic pathway. Chapter 4 describes the use of “metalloligands” as electron-rich building blocks and the subsequent use of the metalloligand for “one-pot” self-assembly reactions in the presence of electron-deficient metal acceptor building blocks. The pyridyl donors are the most preferred in metalloligands because of their predictable directionality in self-assembly. The introduction of a second metal into the ligand component of the self-assembled architecture is to bestow additional functionality as well as to construct elegantly designed discrete heterobimetallic supramolecular architectures. Four discrete Ru(II)-Pt(II) hexanuclear trigonal prismatic cages were synthesized employing a tritopic platinum(II) metalloligand and four p-cymene ruthenium(II) clips via coordination-driven self-assembly. The formation of these cages were confirmed by well-known spectroscopic techniques and their structural features was elucidated by geometry optimization. In vitro anticancer studies of these heterometallic cages failed because of solubility challenges in the culture media presumably due to their high molecular weights and many alkyl groups. Scheme 4: Energy minimized structures of the heterometallic trigonal prismatic cages 3a (left) and 3b (right). Hydrogen atoms have been removed for the sake of clarity [Ru: green, Pt: pink, O: red, N: blue, P: orange, C: grey]. Chapter 5 discusses the synthesis of two bidentate platinum(II) metalloligands as well as the self-assembly of six new heterometallic rectangles obtained from four Ru2(OOꓵOO)2(p-cymene)2Cl2 pillars and two bidentate pyridyl-based platinum(II) metalloligands. The Ru4Pt2 and Ru4Pt4 rectangles were structurally characterized and supported by geometry optimisation. Additionally, two Ru4Pt2 and two Ru4Pt4 rectangles were examined for their anticancer properties in eight human cancer cell lines with the aim of checking if the platinum metal centres in the metalloligands can enhance the anticancer activity of the rectangles. The results showed that these heterometallic rectangles are cytotoxic against the cancer cell lines tested but the incorporation of platinum(II) metal(s) into the metalloligand did not further enhance the cytotoxicity in the rectangles tested as hypothesized. The mechanism of cell death is via the generation of reactive oxygen species (ROS) and two Ru4Pt4 rectangles activates both early and late apoptosis. Cell cycle analysis showed that one of the Ru4Pt4 rectangles is a moderate inhibitor of cell cycle progression at the sub G1 phase similar to cisplatin while nuclear condensation and cell blebbing in the cells was also observed in the presence of the two Ru4Pt4 rectangles tested. The overall activity of the heterometallarectangles against the cancer cell lines tested was increased when they exist as a single entity thus reiterating the importance of heterobimetallic supramolecular architectures in cancer therapy. Scheme 5: Schematic diagram of the discrete Ru4Pt4 heterometallic rectangles and illustration of the cell death pathway. The results of the investigation reported in this thesis contribute to the rapidly developing field of organometallic ruthenium(II) self-assembled anticancer chemotherapeutics with specific evidences of the mechanistic pathway of cell death. This results can further guide the design and development of better chemotherapeutics for future use.