Study of Anti-Cancer and Anti-Viral Activities of Lanthanide and Vanadium Complexes

This dissertation, "Study of Anti-cancer and Anti-viral Activities of Lanthanide and Vanadium Complexes" by Suk-yu, Wong, 黃淑如, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled STUDY OF ANTI-CANCER AND ANTI-VIRAL ACTIVITIES OF LANTHANIDE AND VANADIUM COMPLEXES Submitted by Wong Suk Yu for the degree of Doctor of Philosophy at The University of Hong Kong in September 2006 The use of metal complexes as therapeutic agents for the treatment of cancer, viral infections and diabetes has been extensively studied. As they generally have different mechanisms of activity from organic cytostatic compounds against cancer, the development of metal complexes provides an alternative route to novel anti-cancer drugs. In this study, various lanthanide complexes with porphyrin, polypyridine and Schiff base ligands were synthesized, characterized by X-ray crystallography, and subjected to study their anti-cancer properties. In addition, a series of oxovanadium porphyrin complexes were synthesized, characterized by X-ray crystallography and subjected to study their anti-viral and anti-diabetic properties. The lanthanide(III) porphyrin complexes of [Yb(OEP)(-OH)(H O)] (1a) and 2 2 {[Yb(TPP)] (-C O )(C H O )} (2d) were stable in organic solvents, buffer solution 2 2 4 4 8 2 and physiologically-relevant environments. DNA interaction studies showed that complexes 1a and 2d bound strongly to calf thymus DNA (ct-DNA) with binding 6 -1 3 5 -1 3 constants of (1.59 0.3) 10 mol dm and (5.49 0.8) 10 mol dm, respectively. Thermal denaturation studies with ct-DNA showed that 1a destabilized the duplex structure of DNA. Evidence from gel mobility shift assays indicated that the mode of interactions of 1a and 2d with DNA is non-intercalating in nature. The cytotoxic activities of these lanthanide(III) complexes were investigated in a set of carcinoma cell lines. Lanthanide(III) porphyrin and polypyridyl complexes demonstrated significant cytotoxicity against different types of cancer cells (IC = 50 0.06 M to 3.55 M). It is noteworthy that 1a exhibited similar cytotoxicity towards nasopharyngeal carcinoma cells (SUNE1) and its cisplatin-resistance variant (CNE2) (SUNE1, IC = 2.45 M; CNE2, IC = 3.35 M), suggesting that 1a is capable to 50 50 circumvent cisplatin resistance. Cellular uptake experiments with 1a in human cervical epithelioid carcinoma cells (HeLa) suggested that there is a time- and concentration-dependent intracellular accumulation of ytterbium metal. Transmission electron microscopy and confocal fluorescent microscopy with acridine orange staining suggested the formation of autophagic vesicles. The GFP-LC3 experiments and activation of apoptotic markers proved that 1a induced both autophagic and apoptotic cell death in cancer cells. Significant anti-tumor effect of 1a with 37 % growth inhibition was illustrated in xenograft mice model. The oxovanadium(IV) porphyrin complexes were highly stable in organic solvents, buffer solution and physiologically-relevant environments. Their cytotoxicities against normal human cells were low after 2 - 7 days of treatment. Complex 10 demonstrated notable effects on anti-proliferation of HIV in Hut/CCR5 cells. The vanadyl porphyrins exhibited significant inhibitory effects against reverse transcriptase (RT) and viral replication, and were comparable to the clinically used RT inhibitor nucleoside analogue, AZT. Complex 10 had a low binding specificity to a connection domain sequence 398-407 of RT. Vanadyl porphyrins were fairly ineffective in anti-HBV and anti-diabetes