Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach. Issue 37 (5th August 2016)

• Record Type: Journal Article
• Authors: Chini, Maria G.; Malafronte, Nicola; Vaccaro, Maria C.; Gualtieri, Maria J.; Vassallo, Antonio; Vasaturo, Michele; Castellano, Sabrina; Milite, Ciro; Leone, Antonietta; Bifulco, Giuseppe; De Tommasi, Nunziatina; Dal Piaz, Fabrizio
• Is Part Of: Chemistry. Volume 22:Issue 37(2016)
• Page Start: 13236
• Page End: 13250
• Publication Date: 2016-08-05
• Subjects: ab initio calculations -- antitumor agents -- drug discovery -- inhibitors -- natural products; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201602242
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The identification of inhibitors of Hsp90 is currently a primary goal in the development of more effective drugs for the treatment of various types of multidrug resistant malignancies. In an attempt to identify new small molecules modulating the activity of Hsp90, we screened a small library of tetranortriterpenes. A high‐affinity interaction with Hsp90 inducible form was uncovered for eight of these compounds, five of which are described here for the first time. By monitoring the ATPase activity and the citrate synthase thermal induced aggregation, compound1 (cedrelosin A), 3 (7α‐limonylacetate), and5 (cedrelosin B), containing a limonol moiety, were found to be the most effective in compromising the Hsp90α chaperone activity. Consistent with these findings, the three compounds caused a depletion of c‐Raf and pAkt Hsp90 client proteins in HeLa and MCF/7 cell lines. Induced fit docking protocol and molecular dynamics were used to rationalize the structural basis of the biological activity of the limonol derivatives. Taken together, these results point to limonol‐derivatives as promising scaffolds for the design of novel Hsp90α inhibitors. Abstract : On target : The combination of phytochemical analyses, ab initio (QM/NMR approach) and in silico methods, and in vitro assays has allowed the identification and characterization of new limonol‐derivatives targeting the Hsp90 C‐terminal domain (see figure).