Shi, Huayun (2019) Photoactive diazido platinum(IV) anticancer complexes. PhD thesis, University of Warwick.

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Abstract

This thesis is concerned with the design and mechanism of action of photoactive anticancer drugs. In particular, it focuses on the functionalisation of trans-diazido Pt(IV) complexes by conjugation of the axial ligands to other biologically-active molecules, to vectors and probes, and aims to red-shift the activation wavelength to allow activation deeper in tissues and enhance their cellular accumulation and photocytotoxicity.

In this thesis, photoactive trans-diazido Pt(IV) complexes with a general formula [Pt(N3)2(py)2(OR1)(OR2)] have been synthesised and characterised by NMR, HPLC, ESI-MS, UV-vis and fluorescence spectroscopy, cyclic voltammetry, and X-ray crystallography.
Amino acids are alternative fuels for cancer cells, other than glucose, and thus can be used as targeting vectors in cancer therapy. Complexes 4‒7 labeled with amino acid methyl esters and 8 functionalised with a cyclic peptide, exhibited dark stability and photodecomposition upon irradiation with visible light. Pt-GMP adducts, azidyl and hydroxyl radicals were detected from 4‒6 upon irradiation, while the formation of these photoproducts was quenched by Trp in 7. Significant photocytotoxicity and photoactivated Pt accumulation in A2780 ovarian cancer cells were observed for 4‒8.

Mono-substituted diazido Pt(IV) complexes 9‒12 were compared with their di-substituted analogues 13‒16. As expected, di-substituted complexes displayed longer HPLC retention times and less negative reduction potentials, therefore lower dark stability in aqueous media than the mono-substituted complexes. However, more potent photocytotoxicity and higher cellular accumulation were detected for di-substituted complexes. Dramatic morphological changes in A2780 cells were observed after irradiation with 11. Biotinylated 11 also formed a non-covalent adduct with avidin, which resulted in enhanced photocytotoxicity and cellular accumulation compared with 11 alone.

Fluorescence imaging can be used to monitor the pathway of drug within cells and tissues. Diazido Pt(IV) complexes conjugated to coumarin 19, dansyl 20, 1,8-naphthalimide 21‒23, and trans N=N bond containing azo ligand 24‒26 were prepared. The photodecomposition of 19‒23 with indigo (420 nm) – green (517 nm) light was monitored by the change of UV-vis absorption, LC-MS, EPR and increased fluorescence. Trans-azo ligands in these Pt(IV) complexes can undergo photo-switching to form the cis-azo complexes. Photoreactions with 5’-GMP and photo-oxidation of NADH were observed for these complexes. Complexes 19, 23 and 24‒26 displayed significant photocytotoxicity in cancer cells (465 nm), and 23 is also photocytotoxic with green light (520 nm).

Heteronuclear complexes 27 labelled with ferrocene and 28 with [Ir(ppy)2(bpy-CH2NH2)]Cl have red-shifted absorption bands. Satisfactory dark stability for both complexes, and photodecomposition with long wavelength light (420‒593 nm) for 27 and a fast rate (decomposition within 5 min) for 28 were observed. Azidyl and hydroxyl radicals, singlet oxygen and other ROS in aqueous solution and in cells were detected for both complexes. Low dark cytotoxicity and significantly enhanced photocytotoxicity were observed with longer excitation wavelength and shorter irradiation time. The higher lipophilicity of 27 and positive charge of 28 are regarded as the main reason for their high cellular accumulation. Ruptured nuclear membranes and released chromosomes were observed in A549 cells exposed to 28 and light, indicating its promising photocytotoxity with the synergetic effect of the two different metal centres.

Overall, this work significantly advances the functionalisation of trans-diazido Pt(IV) complexes in axial positions. Cancer-targeting vectors, active anticancer drugs, fluorescent tags, photo-switchable dyes, and metal complexes have been conjugated to trans-diazido Pt(IV) complexes, resulting in photoactivation with long wavelength light, shorter photodecomposition times, enhanced cellular accumulation and photocytotoxicity, and improved photo-induced cellular ROS levels.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Platinum compounds -- Therapeutic use, Cancer -- Photochemotherapy, Photochemotherapy, Ligands (Biochemistry), Fluorescence spectroscopy, Voltammetry, X-ray crystallography
Official Date:	September 2019
Dates:	Date Event September 2019 UNSPECIFIED
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:	pdf
Extent:	xii, 227, vii leaves : illustrations, charts
Language:	eng

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