Antitumor Properties of Some 2-[(Dimethylamino)methyl]phenylgold(III) Complexes

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.

Solution chemistry and cytotoxic properties of novel organogold(III) compounds

“…1 Additional reports on the antitumour properties of selected gold(III) complexes are the result of the research activities of other groups. [2][3][4][5][6] Notably, gold(III) compounds seem to exert their growth inhibitory effects through mechanisms that are distinct from those of the classical anticancer platinum(II) complexes. 7 Among the recently tested compounds, the organogold(III) complex, [Au(bipy dmb -H)(OH)][PF 6 ], characterised by an appreciable stability within physiological conditions, has proved to be very active against the A2780 cell line; 8 at variance with the platinum(II) complexes, its biological activity seems to be unrelated to a direct interference with DNA function and metabolism.…”

Gold(III) compound is a novel chemocytotoxic agent for hepatocellular carcinoma

“…12,13 However, compounds containing gold in the 1III oxidation state tend to be reduced in vivo to gold(I) and metallic gold as the mammalian environment is generally reducing, 14 and many of the currently available gold(III) compounds exhibit poor solubility, or are only effective at relatively high doses. 15 We have recently synthesized a series of gold(III) meso-tetraarylporphyrins that are stable against demetallation in physiological conditions. 16 The porphyrin ligands in these compounds can stabilize the gold(III) center and carry the metal to their cellular targets.…”

Organogold chemistry: III applications

“…similar to cisplatin against a range of tumour lines (43). In tests against the breast tumour line ZR-75-1 grafted onto living mice, it gave similar profiles to cisplatin although at rather higher doses (see Figure 2a).…”

“…The reactivity towards model biological ligands, such as cysteine, glutathione, adenine and adenosine was found to be slightly different from that of cisplatin (44). The formation of inter-and intra-strand links in DNA, however, are not the same as those shown by cisplatin (43), so that the detailed biochemical mechanisms are different; the gold compounds may therefore show a novel spectrum of activity.…”

“…In tests against the breast tumour line ZR-75-1 grafted onto living mice, it gave similar profiles to cisplatin although at rather higher doses (see Figure 2a). The corresponding diacetato complex has much greater aqueous solubility and is rather more effective (see Figure 2b) (43). The analogy to cisplatin is reinforced by the observed hydrolysis behaviour, in which one acetate group is very readily replaced by water, and a second more slowly.…”