Abstract
Gold(I) complexes with phosphine ligands—[Au(TrippyPhos)Cl] (1) (TrippyPhos = 1-[2-[bis(tert-butyl)phosphino]phenyl]-3,5-diphenyl-1H-pyrazole), [Au(BippyPhos)Cl]0.5CH2Cl2 (2) (BippyPhos = 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole), and [Au(meCgPPh)Cl] (3) (meCgPPh = 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane—were investigated as types of bioactive gold metallodrugs. Complexes (1)–(3) were characterized using IR, 1H, 13C, 31P NMR spectroscopy, elemental analysis and mass spectrometry (FAB-MS). Complexes of (1) and (2) exhibited substantial in vitro cytotoxicity (IC50 = 0.5–7.0 μM) against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the A549 human lung carcinoma, K562 chronic myelogenous leukemia, and HeLa (human cervix carcinoma) cells. However, among the compounds studied, complex (2) showed the most promising biological properties: the highest stability in biologically relevant media, selectivity towards cancer cells over the non-cancer cells (HUVEC, human umbilical vein endothelial cells), and the highest inhibitory effect on cytosolic NADPH-dependent reductases in A2780 and A2780cis cells among the gold complexes under analysis.
Highlights
For several decades gold(I) complexes have attracted attention as potential metallodrugs due to their activities targeting pathways involved in cancer development and progression
Auranofin was effective as a cytotoxic agent in cisplatin-resistant human ovarian cancer cells
Phosphine-gold(I) complexes were synthesized by the reaction of of [HAuCl4 ·H2 O]
Summary
Gold(I) complexes have attracted attention as potential metallodrugs due to their activities targeting pathways involved in cancer development and progression. A lead compound among Au(I) complexes—auranofin [2,3,4,6-tetra-oacetyl-1-thio-β-D-glucopyranosato-S-(triethyl-phosphine) gold]—is a thiol-reactive gold(I)containing compound approved by FDA as an anti-arthritic drug. Its anti-tumor effect against cancer in vitro and in vivo models has been recognized. Auranofin inhibited the proliferation and survival of the p53-null ovarian carcinoma SKOV3 cell line [1] suggesting a p53-independent mechanism of auranofin-induced apoptosis. Auranofin was effective as a cytotoxic agent in cisplatin-resistant human ovarian cancer cells. C13*; the anti-proliferative effect of auranofin was accompanied by the inhibition of thioredoxin reductase activity in the cancer cells studied [2]. Since the 1990s, the thioredoxin reductase system has been identified as the primary target of auranofin activity [3]
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