ABSTRACT
It is evident that the chemistry of platinum is in a more advanced state than that of gold, mainly due to the success of the former in several anti-cancer drugs. With a view to finding possible, new candidates with chemotherapeutic potential, the use of sulphur-donor ligands bonded to platinum and gold is discussed herein in an attempt to promote the need to investigate similar ligands. Chloro(2,3-diphenyl-1,3,4-thiadiazolium-5-thiolato-S(exo))gold(I) has been synthesised using a standard reaction, whereby Au(III) is initially reduced to Au(I) then reacted with the ligand, 2,3-diphenyl-1,3,4-thiadiazolium-5-thiolate.hydrochloride, isolated and finally characterised by elemental analyses and infrared spectroscopy. The compound is the first example of gold attached to a meso-ionic compound. It has also been tested for anti-bacterial and anti-fungal activity and shown to possess moderate activity against Gram-positive bacteria, although is inactive against, Gram-negative bacteria and fungi.
ABSTRACT
Four analogues of the gold(III) complex [AuCl2(damp)] (1) (damp = 2-[(dimethylamino)methyl]phenyl) have been evaluated for antitumor activity. The compounds have structural features in common with cisplatin which was included as a comparison in the study. In vitro, against a panel of cell lines established from tumors of different tissue types, the gold complexes showed broadly similar growth inhibitory properties with some selectivity to the HT1376 bladder cell line. In a panel of human ovarian carcinoma cell lines, non-cross-resistance to cisplatin was observed, for the complexes, in an acquired cisplatin-resistant line. In vivo, using subcutaneously implanted xenografts derived from the HT1376 bladder and CH1 ovarian cell lines, [Au(acetato)2(damp)] (3) and [Au(malonato)(damp)] (5) (administered intraperitoneally) gave significant tumor inhibition. Mechanistic studies performed with compound 3 showed marked differences to cisplatin. Thus, much higher concentrations of the gold compound were required to affect Col E1 plasmid mobility, and an alkaline elution study showed that 3 did not cause interstrand DNA cross-links in SK-OV-3 cells. Exposure of SK-OV-3 cells to 3 induced only relatively minor changes in cell cycle distribution. Furthermore 3 was only marginally active in vivo against the cisplatin-sensitive murine ADJ/PC6 plasmacytoma. In summary, the gold-(III) complexes 3 and 5 exhibited selective cytotoxicity in vitro and showed in vivo antitumor activity against human carcinoma xenografts. Also, although 3 has some structural similarity to cisplatin, its mode of action appears to be different.
