Structural characterization of tetranortriterpenes from Pseudrocedrela kotschyi and Trichilia emetica and study of their activity towards the chaperone Hsp90

Piaz, Fabrizio Dal; Malafronte, Nicola; Romano, Adriana; Gallotta, Dario; Belisario, Maria Antonietta; Bifulco, Giuseppe; Gualtieri, María; Sanogo, Rokia; Tommasi, Nunziatina De; Pisano, Claudio

doi:10.1016/j.phytochem.2011.12.002

Cited by 38 publications

(44 citation statements)

References 57 publications

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“…For our studies we referred to a crystal structure of the yeast middle and C-terminal domain determined by Ali et al in 2006 [29], used by us [30] and other research groups [31], and its sequence alignment with the human protein reported by Lee et al [32] for the studies of new Hsp90 inhibitors. During our studies, we considered the lentiginosine octahydro-indolizine ring protonated at physiological pH.…”

Section: Resultsmentioning

confidence: 99%

Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

et al. 2012

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Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and cell viability. The relevance of Hsp90 as a therapeutic target for numerous diseases states has prompted the identification and optimization of novel Hsp90 inhibitors as an emerging therapeutic strategy. We performed a screening aimed to identify novel Hsp90 inhibitors among several natural compounds and we focused on the iminosugar (+)-lentiginosine, a natural amyloglucosidases inhibitor, for its peculiar bioactivity profile. Characterization of Hsp90 inhibition was performed using a panel of chemical and biological approaches, including limited proteolysis, biochemical and cellular assays. Our result suggested that the middle domain of Hsp90, as opposed to its ATP-binding pocket, is a promising binding site for new classes of Hsp90 inhibitors with multi-target anti-cancer potential.

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Section: Resultsmentioning

confidence: 99%

Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

et al. 2012

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“…Amongo thers, the triterpenec elastrol, [50,51] belonging to this class of non-ATP-competitive inhibitors of Hsp90, [52] is able to disrupt the complex between Hsp90 N-terminus and Cdc37. ATPase activity in respectt oN -terminal inhibitors, compounds binding to the protein C-terminal (e.g.,e pigallocatechin-3-gallate) [51] and middle domain (e.g.,k otschyin D) [32,51] have unique effects on the protein conformation and on its interactions with co-chaperones and clients. Inhibition of Hsp90 dimerization.…”

Section: Discussionmentioning

confidence: 99%

“…[32] Based on this data, structurally limonoid-based moleculesh ave been shown to be useful tools for the investigation of the chemical space of the Hsp90 middle and C-terminus domains. [32] Based on this data, structurally limonoid-based moleculesh ave been shown to be useful tools for the investigation of the chemical space of the Hsp90 middle and C-terminus domains.…”

Section: Discussionmentioning

confidence: 99%

“…This experimental strategy was previously used to study other Hsp90/inhibitor complexes. [7,[32][33] Ac omparison between the cleavages ites ob- served on Hsp90a and on Hsp90a/1,H sp90a/3,a nd Hsp90a/5 complexes ( Figure 5) allowed the formulation of some hypothesis on the possible bindingr egion of the three compounds.…”

Section: Identification Of the Hsp90 Regionr Esponsible For Molecularmentioning

confidence: 99%

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Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach

Chini

Malafronte

Vaccaro

et al. 2016

Chemistry A European J

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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.

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“…SPR analyses were carried out according to our previously published procedures [22], [23]. Briefly, SPR analyses were performed using a Biacore 3000 optical biosensor equipped with research−grade CM5 sensor chips (GE Healthcare).…”

Section: Methodsmentioning

confidence: 99%

Identification of the Plant Compound Geraniin as a Novel Hsp90 Inhibitor

et al. 2013

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Besides its function in normal cellular growth, the molecular chaperone heat shock protein 90 (Hsp90) binds to a large number of client proteins required for promoting cancer cell growth and/or survival. In an effort to discover new small molecules able to inhibit the Hsp90 ATPase and chaperoning activities, we screened, by a surface plasmon resonance assay, a small library including different plant polyphenols. The ellagitannin geraniin, was identified as the most promising molecule, showing a binding affinity to Hsp90α similar to that of 17-(allylamino)-17-demethoxygeldanamycin (17AGG). Geraniin was able to inhibit in vitro the Hsp90α ATPase activity in a dose−dependent manner, with an inhibitory efficiency comparable to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90α, monitored by the citrate synthase thermal induced aggregation assay. Geraniin decreased the viability of HeLa and Jurkat cell lines and caused an arrest in G2/M phase. We also proved that following exposure to different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, and EGFR was strongly down−regulated in both the cell lines. These results, along with the finding that geraniin did not exert any appreciable cytotoxicity on normal cells, encourage further studies on this compound as a promising chemical scaffold for the design of new Hsp90 inhibitors.

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Structural characterization of tetranortriterpenes from Pseudrocedrela kotschyi and Trichilia emetica and study of their activity towards the chaperone Hsp90

Cited by 38 publications

References 57 publications

Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach

Identification of the Plant Compound Geraniin as a Novel Hsp90 Inhibitor

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