Hydrosulfide Adducts of Organo-Iridium Anticancer Complexes

Novel half-sandwich hydrosulfidoiridium(III) complexes [(η5-Cp*)Ir(phen)(SH)]PF6 (1), [(η5-Cp*)Ir(bpy)(SH)]PF6 (2), [(η5-Cpbiph)Ir(phen)(SH)]PF6 (3), and [(η5-Cpbiph)Ir(bpy)(SH)]PF6 (4) were prepared from the chlorido complexes by dechlorination and treatment with excess NaSH·xH2O; phen = 1,10-phenanthroline, bpy = 2,2′-bipyridine, Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl, and Cpbiph = 1,2,3,4-tetramethyl-5-biphenylcyclopentadienyl. Complexes 1–4 were characterized by various techniques including electrospray ionization mass spectrometry, NMR spectroscopy (δ(SH) ca. −2 ppm), and a single-crystal X-ray analysis. Complex [(η5-Cp*)Ir(phen)(SH)]BPh4 (1′) shows a typical piano-stool geometry with Ir–S bond length of 2.388(2) Å. Cpbiph complexes 3 (IC50 = 0.98 μM) and 4 (IC50 = 0.61 μM) showed significantly higher (p < 0.005) in vitro antiproliferative activity against A2780 human ovarian cancer cells, as compared with their Cp* analogues 1 (IC50 = 49.5 μM) and 2 (IC50 = 48.4 μM), and potency similar to the anticancer drug cisplatin. The complexes were relatively stable in aqueous solution toward hydrolysis and reactions with reduced glutathione (GSH), 9-ethylguanine, or 9-methyladenine. Interestingly, GSH was readily oxidized to glutathione disulfide in the presence of Cpbiph complexes 3 and 4, as judged by 1H NMR, perhaps indicative of a possible redox-linked mechanism of action.