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This thesis focuses on the development of gold- and non-classical platinum-based anti-cancer agents that display distinctively different anti-cancer mechanisms compared to the commonly used cisplatin. These metal complexes contain N-heterocyclic carbene (NHC) ligands which are able to form strong M-C(NHC) bonds, conferring high stability and favorable lipophilicity, reactivity and binding specificity of metal complexes on biomolecules. The author demonstrates significant advances made in anti-cancer gold(III), gold(I) and platinum(II) complexes. Detailed chemical synthesis, in vitro and/or in vivo anti-cancer activities are clearly presented including: (i) a class of Au(III) complexes containing a highly fluorescent N^N^N ligand and NHC ligand that simultaneously act as fluorescent thiol switch-on probes and anti-cancer agents; (ii) a dinuclear gold(I) complex with a mixed diphosphine and bis(NHC) ligand displaying favorable stability and showing significant inhibition of tumor growth in two independent mice models with no observable side effects; and (iii) a panel of stable luminescent cyclometalated platinum(II) complexes exhibiting high specificity to localize to the endoplasmic reticulum (ER) domain, inducing ER stress and cell apoptosis. These works highlight the clinical potential that gold and platinum complexes offer for cancer treatment.
by The University of Hong Kong as an outstanding Ph.D. thesis reviews the current status of gold- and platinum-based anti-cancer agents Highlights the significant advances made in the area of metal-based anti-cancer agents Includes original drug design, drug synthesis, cell-based bio-experiments and animal-based studies Includes supplementary material: sn.pub/extras
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Introduction.- Experimental Section.- Gold(III) Complexes Containing N-Heterocyclic Carbene Ligand Serve as Dual Fluorescent Thiol Switch-on Probe and Anti-Cancer Agent.- A Binuclear Gold(I) Complex with Mixed Bridging Diphosphine and Bis(N-Heterocyclic Carbene) Ligands Shows Favorable Thiol Reactivity and Effectively Inhibits Tumor Growth and Angiogenesis in Vivo.- Luminescent Organoplatinum(II) Complexes Containing Bis(N-Heterocyclic Carbene) Ligands Selectively Target Endoplasmic Reticulum and Induce Potent Phototoxicity.- Summary and Evaluation.