Abstract
Abstract 1: A tripodal ligand (L1) was synthesized capable of self-assembling into a mononuclear complex [L1M]2+ when reacted with a first-row transition metal (M = Fe2+, Co2+ or Ni2+) and a trinuclear cryptand complex [(L1)2M3(A)]3/4+ when also in the presence of a templating anion (A = PO43- or SO42-). Whilst Fe2+ and Co2+ readily formed the trinuclear complex, Ni2+ required heating due to the inert nature of the metal. The trinuclear complexes of Fe2+ and Co2+ showed significant toxicity towards all cancer cell lines in vitro particularly HCT116-/- for [(L1)2Fe3]6+ and MiaPaCa2 for [(L1)2Co3]6+. The addition of phosphate did not significantly change the toxicity of most of the cell lines with the exception of [(L1)2Co3]6+ against the H460 and [(L1)2Fe3]6+ against the A549 which both became more toxic after the addition of phosphate. Both complexes, with and without phosphate, showed similar or greater selectivity towards the cancer cells over healthy cells for most cell lines with the exceptions being [(L1)2Co3]6+ and [(L1)2Co3(PO4)]3+ which both showed 10-fold greater selectivity towards the healthy cells. For all cell lines Ni2+ showed no significant toxicity, attributed to the inert nature of Ni2+. Against the cell lines HCT116+/+, HCT116-/- and MiaPaCa2, the Fe2+ and Co2+ complexes showed a significant improvement over the platinates (considered the ‘standard of care’) with both higher toxicity and selectivity values showing up to 47-fold higher selectivity towards cancer cells over healthy cells. In hypoxic conditions the Co2+ complexes displayed significantly reduced toxicity with a 4-fold decrease in chemotoxicity, whilst the Fe2+ complexes showed only a minor reduction in toxicity. In CAM testing this toxicity did not persist with no significant reduction in size of the tumour compared to the control.Abstract 2: A tripodal ligand (L2) was synthesized which was incapable of self-assembling into a mononuclear or trinuclear complex when reacted with a first-row transition metal (Zn2+ or Cu2+) and a templating anion (PO43-). Instead, a mixture of unknown polymers was produced, forming a gel like material, which is attributed to the lack of preorganization of the ligand making it unable to form the expected cryptand cage. When tested against various in vitro cell lines, no significant cytotoxicity was seen likely due to the biologically inert nature of the unknown polymers produced.
Abstract 3: A bipodal ligand (L3) was synthesized capable of self-assembling into a dinuclear helicate complex [(L3)2M2]4+ when reacted with a first-row transition metal (M = Zn2+, Cu2+ or Mn2+) both in the presence and absence of a templating anion (PO43- or SO42-). In the absence of a templating anion, each metal ion was 6-coordinate whereas the presence of an anion causes one metal to become 5-coordiante. All three complexes, [(L3)2Zn2]4+, [(L3)2Cu2]4+ and [(L3)2Mn2]4+, were shown to possess significant cytotoxicity against in vitro cancer cell lines whilst also being highly selective towards the cancerous cells over healthy cells, with the Zn2+ complex showing the greatest SI of 439.58 for the H460 cancer cell line. When compared to the platinates, against the cell lines HCT116+/+, HCT116-/- and MiaPaCa2, all three complexes were shown to possess both higher toxicity and selectivity with the [(L3)2Zn2]4+ complex being up to 138-fold more selective towards cancer cells than the platinates. When [(L3)2Zn2]4+ and [(L3)2Cu2]4+ was tested against the CAM model, the Zn2+ complex was shown to not be fully soluble in the solvent system and thus the concentration added was unknown, however, this reduced the size of the treated tumour by 40% compared to the control. The Cu2+ complex was fully soluble in the solvent system but did not show any significant reduction in the size of the treated tumour.
Abstract 4: A series of Ru(II)-containing complexes [(bipy)2Ru(L4-7)]2+ were synthesized which undergo photodissociation of the of the 3,3ʹ-disubstituted-2,2ʹ-bipyridine ligand. The presence of dihydrogen phosphate significantly decreased the rate of photodissociation of the ligand in addition to the photochemical quantum yield. This observed change was attributed to an intermolecular allosteric effect caused by the interactions between the anion and amide groups on the 3,3ʹ-disubstituted-2,2ʹ-bipyridine ligand. Ligand L8 contains a disubstituted bipyridine moiety with an appended tetraaza-crown unit which forms the Ru(II)-containing complex [(bipy)2Ru(L8)]2+ and was shown to not exhibit significant photodissociation under ambient or intense light. A Zn2+ ion can coordinate to the nitrogen atoms of the aza-crown unit to give the complex [(bipy)2Ru(L8)Zn]2+ which is able to readily undergo ligand photodissociation. The “switching on” of photochemical behavior in the presence of a cation is also attributed to allosteric effects. Both examples show how small molecules, such as anions and cations, can allosterically modify ligand ejection by interacting with a remote part of a complex. When complexes [(bipy)2Ru(L4-8)]2+ were examined against a series of in vitro cell lines both in the presence and absence of a coordinating ion, no significant cytotoxicity was observed. This was attributed to the complex nature of cells inhibiting the formation of the active species or its ability to reach the DNA.
| Date of Award | 5 Feb 2024 |
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| Original language | English |
| Sponsors | EPSRC-DTP University of Huddersfield (EP/R513234/1) |
| Supervisor | Marco Molinari (Main Supervisor) & Craig Rice (Co-Supervisor) |