Radester, a novel inhibitor of the Hsp90 protein folding machinery.
[reaction: see text]. The antitumor antibiotics radicicol and geldanamycin are potent inhibitors of the Hsp90 protein folding machinery. Radester is a hybrid composed of radicicol's resorcinol ring and geldanamycin's quinone through an isopropyl ester. Radester was prepared, and the cytotoxicity of it and the corresponding hydroquinone were determined in MCF-7 breast cancer cells to be 13.9 and 7.1 microM, respectively. Protein degradation assays were performed on Hsp90-dependent client proteins, Her-2 and Raf, to correlate Hsp90 inhibition to cytotoxicity.
Shen
Gang
G
Department of Medicinal Chemistry and The Center for Protein Structure and Function, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7562, USA.
Blagg
Brian S J
BS
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016227:Benzoquinones; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic; D010084:Oxidation-Reduction; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D016227:Benzoquinones; C501629:G3130; D018841:HSP90 Heat-Shock Proteins; C507938:KOSN1559; D047029:Lactams, Macrocyclic; D010636:Phenols; D011720:Pyrazoles; D011809:Quinones; C507937:radester; C001277:geldanamycin