Luminescent platinum(II), gold(III), and iridium(III) complexes for biological studies : anti-cancer, sensing, and bioimaging

Abstract

Interpretation of the expression, localization, and properties of biomolecules is an important goal in chemical biology research, and appropriate biomarkers have thus been developed over the years. Luminescent transition metal complexes possess several remarkable advantages rendering them promising candidates for biological studies. In this thesis, luminescent complexes of transition metals platinum(II), gold(III), and iridium(III) for anti-cancer, sensing, and bioimaging have been developed. A series of luminescent cyclometalated platinum(II) isocyanide complexes [PtII(C^N^Npyr)(C≡NR)]+ (HC^N^Npyr = 2-phenyl-6-(1H-pyrazol-3-yl)-pyridine), including [PtII(C^N^Npyr)(C≡N-2,6-Me2C6H3)]+ (3.1, HC≡N-2,6-Me2C6H3 = 2,6-dimethylphenyl isocyanide), have been synthesized and characterized. These complexes show pH-sensitive phosphorescence in aerated aqueous solutions and trend to self-assemble in low pH. Owing to the low pH induced self-assembly of the platinum(II) complexes, they were found to be selectively accumulated in low pH lysosomes (pH ~5) in living HeLa (human cervical cancer) cells and the accumulation has led to lysosome dysfunction which contributed to their cytotoxicity towards cancer cells. Among the synthesized [PtII(C^N^Npyr)(C≡NR)]+ complexes, complex 3.1 was found to form a supramolecular gel (3.1-hydrogel) in water. Under physiological conditions, the 3.1-hydrogel exhibited a sustained-release anti-cancer property and the release activity can be motivated by acidic environment. In addition, the anti-cancer 3.1-hydrogel can act as a drug carrier to deliver other therapeutic agents to achieve dual therapeutic effects. Cyclometalated gold(III) complex, [AuIII(C^N^C)(NHC-R)]+ (4.1; HC^N^C = 2,6-di(naphthalene-2-yl-)pyridine; NHC-R = biotinylated 1-mesityl-1H-imidazole), bearing a biotin moiety has been designed and characterized. Complex 4.1 is non-emissive in an aerated aqueous medium as a result of its extraordinarily long emission lifetime. Upon incorporation with protein avidin, the resulting gold(III) avidin conjugate (conjugate 4.1) was found to be emissive with a lifetime of 1.8 μs in an aerated aqueous medium. Moreover, the conjugate 4.1 has been used in the staining of proteins and DNA strands and showed a good linearity range (R = 0.99). The staining property of the conjugate 4.1 was also found to be concentration- and/or size-dependent. Cytotoxicity evaluation of the conjugate 4.1 towards several cancer cell lines revealed that it displays anti-proliferative activities and can induce the apoptosis of HeLa cells. In the case of luminescent iridium(III) complexes, a panel of cyclometalated [IrIII(C^N)2(N^N)]+ complexes containing a diazo moiety have been synthesized and used as diazo agents for carbene transfer reaction mediated by [RuII(4-Glc-TPP)(CO)] (5.1; 4-Glc-TPP = meso-tetrakis(4-(β-D-glucosyl)phenyl)porphyrinato dianion) in selective cysteine modification of peptides under physiological conditions (H2O/dioxane (9:1), r.t., 3 h). Modifications of the internal or terminal cysteine-containing peptides using the present approach resulted in product conversions of 43–99%. As supported by liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis, the modifications occurred exclusively at the cysteine residue of the peptides. The present carbene transfer reaction was also achieved in living HeLa cells for selective cysteine modification of intracellular glutathione with the confirmation of LC-MS/MS studies. In addition, by using complex [IrIII(C^N)2(N^N)]+ wherein HC^N = 2-phenylpyridine and HN^N = 8-(4'-methyl-[2,2'-bipyridine]-4-carboxamido)octyl 2-diazoacetate (complex 5.4) as diazo agent, the 5.4-modified HTDP (a cell penetrating peptide) which was generated using the present approach can be utilized for bioimaging studies. (494words)