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Bioorg Med Chem Lett ; 28(13): 2289-2293, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29807796

ABSTRACT

TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.


Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/pharmacology , Mitochondria/metabolism , Adenosine Triphosphatases/antagonists & inhibitors , Apoptosis/drug effects , Cell Proliferation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guanidines/chemical synthesis , Guanidines/chemistry , Guanidines/pharmacology , HCT116 Cells , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Molecular Structure , Onium Compounds/chemical synthesis , Onium Compounds/chemistry , Onium Compounds/pharmacology , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Pyridinium Compounds/chemical synthesis , Pyridinium Compounds/chemistry , Pyridinium Compounds/pharmacology
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