The Library
Organometallic iridium and rhodium anticancer complexes
Tools
Zhang, Wenying (2020) Organometallic iridium and rhodium anticancer complexes. PhD thesis, University of Warwick.
|
PDF
WRAP_Theses_Zhang_2020.pdf - Submitted Version - Requires a PDF viewer. Download (11Mb) | Preview |
Official URL: http://webcat.warwick.ac.uk/record=b3714822
Abstract
The use of clinical drug cisplatin is hampered by the severe toxic side effects due to lack of tumor-specificity and the emergence of platinum resistance. Group 9 metal iridium/rhodium complexes with novel mechanisms of action are promising alternatives to cisplatin. This thesis is focused on the chemical and biological studies on half-sandwich organo-IrIII and organo-RhIII anticancer complexes of the type [(ƞ5- CpX)M(XY)Z] (CpX = pentamethylcyclopentadienyl Cp*, 1-phenyl-2,3,4,5- tetramethylcyclopentadienyl Cpxph, 1-biphenyl-2,3,4,5-tetramethylcyclopentadienyl Cpxbiph, M = Ir/Rh, Z = Cl/I/pyridine).
Eight iodido IrIII complexes [(ƞ5-CpX)Ir(5-R2-pyridylazo-4-R1-phenyl)I]PF6 featuring a strong π-acceptor azopyridine ligand (CpX = Cp* or Cpxph; R1 = Br, CF3, or H; R2 = OH, or H) have been synthesised and characterised.
Six X-ray crystal structures showing a typical “piano-stool” configuration have been determined. Most iridium complexes exhibited higher antiproliferative activity than cisplatin against human A549 lung cancer cells with the most potent complex 3 (Cp*, R1 = OH, R2 = Br) approximately 10 times more active. Despite their inertness toward aquation, iodido complexes can undergo redox activation by attack of the abundant intracellular tripeptide glutathione (GSH) on the chelated azopyridine ligand to generate paramagnetic intermediates, and hydroxyl radicals, together with thiolate-bridged dinuclear iridium complexes and liberated reduced hydrazopyridine ligand. DFT calculations provided insight into the mechanism of this activation. GS- attack on the azo bond facilitates the substitution of iodide by GS-, and leads to formation of GSSG and superoxide if O2 is present as an electron-acceptor, in a largely exergonic pathway. Reaction of iodido complexes with GSH generates [(Cp*)Ir(azopyridine)SG] complexes, which are catalysts for GSH oxidation. The complexes promoted elevated levels of reactive oxygen species (ROS) in human lung cancer cells. Six half-sandwich RhIII cyclometalated complexes [(CpX)Rh(C^N)Z]0/+ (where CpX = Cp*, Cpxph, or Cpxbiph, C^N = benzo[h]quinoline, and Z = Cl or pyridine) were synthesised and characterised. Three X-ray crystal structures show the expected “piano-stool” configurations. The chlorido complexes hydrolyze faster in aqueous solution, react with 9-ethylguanine to a large extent, and react much faster with glutathione compared to their pyridine analogues. The chlorido complex [(Cpxbiph)Rh(benzo[h]quinoline)Cl] (3a) is the most efficient catalyst in oxidizing reduced coenzyme nicotinamide adenine dinucleotide (NADH) to NAD+ and induces an elevated level of reactive oxygen species (ROS) in A549 human lung cancer cells. The pyridine complex [(Cpxbiph)Rh(benzo[h]quinoline)py]+ (3b) is the most potent against human A549 lung and A2780 ovarian cancer cell lines, being 5-fold more active than cisplatin towards A549 cells, but acted as a ROS scavenger.
Three half-sandwich IrIII complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'- bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC) were synthesised and characterised. The ‘piano-stool’ configuration of complex Ir-I was confirmed by its X-ray structure. Significantly, copper-free click strategy were developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. Complex Ir-I was inactive towards human A2780 ovarian cancer cells, whist complex Ir-II exhibited moderate cytotoxic activity.
Classes of novel half-sandwich IrIII complexes conjugated to a ferrocene group or a luminescent probe anthracene, BODIPY, or cyclometalated iridium were synthesised and characterised. The structure of half-sandwich complex 4 bearing one ferrocene group was determined by X-ray crystallography. The ferrocene/ferricenium couple becomes more difficult to oxidize in the iridium complexes compared to free ferrocene. The ferrocene-conjugated chlorido complexes also exhibited slightly lower antiproliferative activity than the analogues without ferrocene conjugation towards human A2780 ovarian cancer cells. Half-sandwich iridium complexes bearing a tridentate dipicolyamine ligand conjugated to an anthracene or a BODIPY group, are inert toward reactions with the biomolecules (GSH and 9-EtG), and show characteristic emissions of the conjugated anthracene or BODIPY fluorophore. Meanwhile, the BODIPY-containing complex [(Cp*)Ir(Bdp-Dpa)](NO3)2 (10) was found to localize mainly in the mitochondria of human ovarian A2780 cancer cells. Its photocytotoxicity is higher than that of anthracene-conjugated complex [(Cp*)Ir(An-Dpa)](PF6)2 (7), which makes it a superior phototherapeutic agent. Phototoxic half-sandwich iridium complex [(ppy)2Ir(Ppy-Phen)(Cp*Ir)Cl]Cl (12) conjugated to a cyclometalated iridium unit, has more than 33-fold lower cytotoxicity in the dark than the cyclometalated complex [(ppy)2Ir(Ppy-Phen)]Cl (11) towards human A2780 ovarian cancer cells, suggesting a greater potential of 12 to kill cancer cells selectively under area-targeted light irradiation. Meanwhile, its photocatalytic turnover frequency (TOF) in catalyzing NADH oxidation is 2-3x higher than that of complex 11 or complex [(Cp*)Ir(ppy)Cl] (13).
Item Type: | Thesis (PhD) | ||||
---|---|---|---|---|---|
Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology |
||||
Library of Congress Subject Headings (LCSH): | Organoiridium compounds -- Therapeutic use, Organorhodium compounds -- Therapeutic use, Antineoplastic agents, Cancer -- Treatment -- Research, Cisplatin -- Therapeutic use | ||||
Official Date: | March 2020 | ||||
Dates: |
|
||||
Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Sadler, P. J. | ||||
Sponsors: | University of Warwick. Chancellor's International Scholarship | ||||
Format of File: | |||||
Extent: | xxi, 295 leaves : illustrations | ||||
Language: | eng |
Request changes or add full text files to a record
Repository staff actions (login required)
View Item |
Downloads
Downloads per month over past year