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Anticancer Gold(III) Porphyrins Target Mitochondrial Chaperone Hsp60
Author(s) -
Hu Di,
Liu Yungen,
Lai YauTsz,
Tong KaChung,
Fung YiMan,
Lok ChunNam,
Che ChiMing
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201509612
Subject(s) - chaperone (clinical) , chemistry , hsp60 , heat shock protein , porphyrin , gold compounds , in vitro , biophysics , ligand (biochemistry) , biochemistry , combinatorial chemistry , hsp70 , biology , receptor , medicine , pathology , gene
Identification of the molecular target(s) of anticancer metal complexes is a formidable challenge since most of them are unstable toward ligand exchange reaction(s) or biological reduction under physiological conditions. Gold(III) meso ‐tetraphenylporphyrin ( gold‐1 a ) is notable for its high stability in biological milieux and potent in vitro and in vivo anticancer activities. Herein, 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‐shock protein 60 (Hsp60), a mitochondrial chaperone and potential anticancer target, is a direct target of gold‐1 a 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.