Tuning the characteristics of quadruply-stranded palladium(II) cages
This thesis consists of five chapters. Chapter 1 gives an introduction into the threat posed to human health by cancer, and the inorganic anti-cancer drug, cisplatin. The disadvantages of this drug are described, as are the benefits of drug delivery to the tumour within a larger vector. The basic principles and strategies of metallosupramolecular synthesis are then laid out, and potential applications where they act as a host to an internally encapsulated guest are discussed. A cisplatin-encapsulating [Pd2(L)4]4+ cage developed by the Crowley group is introduced, and the goals of this project are named; being an investigation into the biological stability of this system, and a study into increased functional scope and complexity for these systems. Chapter 2 introduces the role of metallosupramolecular architectures as cytotoxic agents, and the reliance of this activity on their stability in biological conditions. Work improving the stability of [M2(L)3]n+ cylinders using oxidation of the cobalt metal ions from +2 to +3 is described. The assessment of ligand donor strength in [Pd2(L)4]4+ architectures using a carbene palladium(II) 13C NMR probe is discussed, as are stability testing of the complexes through competition experiments against biological nucleophiles. A trend between donor strength and stability is established, but steric protection of the palladium(II) metal ion is also found to be necessary for these systems. The most stable compound is built from a hexyl-substituted, 1,3-phenyl linked bis-triazole ligand, and this compound demonstrates high cytotoxicity. Tripyridyl [Pd2(L)4]4+ cages were also kinetically stabilised through amino substitution in the 2-position, but this increase in stability unfortunately was at the cost of the capacity to bind cisplatin. Chapter 3 discusses controllable and reversible release and reuptake of guests from metallosupramolecular cages. The addition of chloride to a [Pd2(L)4]4+ cage is found to switch the cage into an open [Pd2(L)2Cl4] macrocycle and free ligand. Silver(I) can be used to strip the chloride anions back off to reform the cage. Two guests that interact with the cage (cisplatin which binds within the cage cavity, and mesylate which binds on the external face of the palladium(II) metal ions) can be present during the switching process, and are released upon formation of the metallacycle and taken up anew upon reformation of the cage. Chapter 4 details the types of self-sorting that have been investigated in palladium(II) architectures, and notes the difficulty in cleanly and controllably accessing heteroleptic structures. A series of competition experiments are then discussed, in which it is shown that introduction of the 2-amino ligand introduced in chapter 2 to a preformed unsubstituted [Pd2(L)4]4+ cage brings about displacement of two of the unsubstituted tripyridyl ligands. Consideration of NMR spectroscopic evidence in tandem with DFT calculations suggests that it is the cis isomer that is formed, and that this product is a highly stable kinetic product energetically uphill from the tetra-substituted product. Chapter 5 introduces larger metallosupramolecular achitectures that have been used to bind multiple guests, in some cases with simultaneous binding of different guest types. While excellent examples of complementary multiple guest-binding within a single architecture have been reported, encapsulation of different guests in an independent fashion have not. An approach using polytopic ligands which forms quadruply stranded palladium(II) cages with multiple cavities is detailed, and used to form a triple cavity cage in which the peripheral cavities have an internally directed pyridyl core, and the central cavity has a phenyl core. It is shown that the peripheral cavities bind cisplatin, while triflate binds in the central cavity, and to the exohedral faces of the cage. Simultaneous segregated guest binding is demonstrated in the presence of both guests.
Advisor: Crowley, James D
Degree Name: Doctor of Philosophy
Degree Discipline: Department of Chemistry
Publisher: University of Otago
Keywords: Metallosupramolecular; Inorganic chemistry; Palladium(II)
Research Type: Thesis