854261-07-7Relevant academic research and scientific papers
Design, synthesis, and structure - Activity relationships for chimeric inhibitors of Hsp90
Shen, Gang,Wang, Mingwen,Welch, Timothy R.,Blagg, Brian S. J.
, p. 7618 - 7631 (2007/10/03)
(Chemical Equation Presented) Inhibition of the 90 kDa heat shock protein (Hsp90) family of molecular chaperones represents a promising new chemotherapeutic approach toward the treatment of several cancers. Previous studies have demonstrated that the natural products, radicicol and geldanamycin, are potent inhibitors of the Hsp90 N-terminal ATP binding site. The cocrystal structures of these molecules bound to Hsp90 have been determined, and through molecular modeling and superimposition of these ligands, hybrids of radicicol and geldanamycin have been designed. A series of macrocylic chimeras of radicicol and geldanamycin and the corresponding seco-agents have been prepared and evaluated for both antiproliferative activity and their ability to induce Hsp90-dependent client protein degradation.
Radester, a novel inhibitor of the Hsp90 protein folding machinery
Shen, Gang,Blagg, Brian S. J.
, p. 2157 - 2160 (2007/10/03)
(Chemical Equation Presented) 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 μM, respectively. Protein degradation assays were performed on Hsp90-dependent client proteins, Her-2 and Raf, to correlate Hsp90 inhibition to cytotoxicity.
