Synthesis and biological evaluation of thiolate gold(i) complexes as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors†
Abstract
New gold(I) thiolate complexes [(PPh2py)Au(SR)] (PPh2py = 2-(diphenylphosphino)pyridine and SR = the deprotonated form of pyridine-2-thiol (HSpy, 1a), pyrimidine-2 thiol (HSpyN, 1b), benzothiazole-2-thiol (HSbt, 1c) and 2-thiazoline-2-thiol (HSt, 1d)) were prepared by the reaction of chloro gold complex [(PPh2py)AuCl], A, with the corresponding in situ generated thiolate salt (through a nucleophilic substitution reaction) under inert conditions. All complexes are characterized by NMR spectroscopy and the structures of 1b and 1d were further identified by single crystal X-ray determination. An in vitro cytotoxicity evaluation against five human cancer cell lines including A549 (nonsmall cell lung cancer), SKOV3 (human ovarian cancer), MCF-7 (human breast cancer), SW1116 (colon cancer) and HeLa (cervical cancer) demonstrated the promising antitumor effects of 1b in comparison with standard auranofin and cisplatin. The effects of these compounds on the proliferation of non-tumoral breast cell line MCF-12A showed good selectivity among tumorigenic and non-tumorigenic cell lines. The results illustrated that 1b effectively produces cell death by inducing apoptosis in the MCF-7 human breast cancer cell line. These complexes inhibit both cytosolic (TrxR1) and mitochondrial (TrxR2) thioredoxin reductases as well as glutathione reductase (GR).
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