title: Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach.
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, compound 1 (cedrelosin A), 3 (7α-limonylacetate), and 5 (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.
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.
authors: Maria G
authors: http://orcid.org/0000-0002-3943-5883
authors: MG
authors: Chini
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.
authors: Nicola
authors: http://orcid.org/0000-0001-5649-3084
authors: N
authors: Malafronte
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.
authors: Maria C
authors: MC
authors: Vaccaro
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.|Department of Pharmacognosy and Organic Drug, University of Los Andes, Sector Campo de Oro, detrás del IAHULA, 5101, Mérida, Venezuela.
authors: Maria J
authors: MJ
authors: Gualtieri
authors: Department of Science, University of Basilicata, Viale dell'Ateneo Lucano 10, 85100, Potenza, Italy.
authors: Antonio
authors: http://orcid.org/0000-0001-7937-3309
authors: A
authors: Vassallo
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.|PhD Program in Drug Discovery and Development, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.
authors: Michele
authors: M
authors: Vasaturo
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.|Department of Medicine and Surgery, University of Salerno, Via Allende, 84081, Baronissi, Italy.
authors: Sabrina
authors: http://orcid.org/0000-0002-7449-3704
authors: S
authors: Castellano
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.
authors: Ciro
authors: http://orcid.org/0000-0003-1000-1376
authors: C
authors: Milite
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.
authors: Antonietta
authors: http://orcid.org/0000-0002-7236-8010
authors: A
authors: Leone
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. bifulco@unisa.it.
authors: Giuseppe
authors: http://orcid.org/0000-0002-1788-5170
authors: G
authors: Bifulco
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy. detommasi@unisa.it.
authors: Nunziatina
authors: http://orcid.org/0000-0003-1707-4156
authors: N
authors: De Tommasi
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Italy.|Department of Medicine and Surgery, University of Salerno, Via Allende, 84081, Baronissi, Italy.
authors: Fabrizio
authors: http://orcid.org/0000-0002-8643-5018
authors: F
authors: Dal Piaz
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002470:Cell Survival; D036604:Chromolaena / Q000737:chemistry; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D010936:Plant Extracts / Q000737:chemistry*; D018515:Plant Leaves / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D010936:Plant Extracts; D054852:Small Molecule Libraries; D014315:Triterpenes; D002950:Citrate (si)-Synthase; D000251:Adenosine Triphosphatases
keywords: ab initio calculations; antitumor agents; drug discovery; inhibitors; natural products