Anticancer Gold(III) Porphyrins Target Mitochondrial Chaperone Hsp60

Abstract

Identification of the molecular target(s) of anticancer metal complexes is aformidable challenge since most of them are unstable towardl igand exchange reaction(s) or biological reduction under physiological conditions.Gold(III) meso-tetraphenylporphyrin (gold-1 a)i sn otable for its high stability in biological milieux and potent in vitro and in vivo anticancer activities.H erein, extensive chemical biology approaches employing photo-affinity labeling,click chemistry, chemical proteomics,cellular thermal shift, saturation-transfer difference NMR, protein fluorescence quenching, and protein chaperone assays were used to provide compelling evidence that heat-shockprotein 60 (Hsp60), amitochondrial chaperone and potential anticancer target, is ad irect target of gold-1 a in vitro and in cells.S tructure-activity studies with ap anel of non-porphyrin gold(III) complexes and other metalloporphyrins revealed that Hsp60 inhibition is specifically dependent on both the gold(III) ion and the porphyrin ligand.

Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cells

“…19,20 A similar strategy showed the mitochondrial heat shock protein 60 as a target for gold(III) porphyrins. 21 Furthermore, putative targets for RAPTA compounds were suggested by a target profiling approach. 22 Target profiling experiments are based on affinity purification strategies by immobilizing a drug candidate on a solid support and the subsequent sampling of directly bound protein targets.…”

Supermolecules as Medicinal Drugs

“…Herein, extensive chemical biology approaches employing photo-affinity labeling, click chemistry, chemical proteomics, cellular thermal shift, saturation-transfer difference, nuclear magnetic resonance imaging (NMR), protein fluorescence quenching, and protein chaperone assays were used to provide compelling evidence that heat-shock protein 60 (Hsp60), a mitochondrial chaperone and potential anticancer target, is a direct target of 6 in vitro and in cells. Structure-activity studies with a panel of non-porphyrin gold(III) complexes and other metalloporphyrins revealed that Hsp60 inhibition is specifically dependent on both the gold(III) ion and the porphyrin ligand [22].…”

Water-soluble Manganese and Iron Mesotetrakis(carboxyl)porphyrin: DNA Binding, Oxidative Cleavage, and Cytotoxic Activities

“…So far, lots of metal (Ag, Zn, Co, Ni, Pb, Fe, Mn, Cu, Au, Hg, Cd) cationic porphyrin complexes have been synthesized and tested as potential chemotherapeutical agents [ 6 , 20 , 21 , 22 , 23 , 24 ], and even showed higher potency than cisplatin [ 25 , 26 ]. Meanwhile, anionic sulfonated porphyrins have been known exhibit highly efficient in internalizing and eliciting severe damage in cancer cells upon photo irradiation [ 27 ]. What’s more, they also have the activity against the human immunodeficiency virus (HIV-1) [ 28 ], and strong phototoxic effect against Tobacco Bright Yellow-2-cells [ 29 ].…”

“…Anionic carboxyl porphyrins also show good DNA binding and cleavage activity [ 30 , 31 , 32 ]. However, less information about biological studies on anionic porphyrins are available [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Previous studies have confirmed that anionic porphyrins have better membrane permeability than cationic ones [ 35 , 36 , 37 ], which may explain their higher biological activity.…”