Targeting the Hsp90 C-terminal domain by the chemically accessible dihydropyrimidinone scaffold

Strocchia, Maria; Terracciano, Stefania; Chini, Maria Giovanna; Vassallo, Antonio; Vaccaro, Maria Carmela; Piaz, Fabrizio Dal; Leone, Antonietta; Riccio, Raffaele; Bruno, Ines; Bifulco, Giuseppe

doi:10.1039/c4cc10074c

Cited by 32 publications

(31 citation statements)

References 38 publications

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“…These results are confirmed by only few past experiences, in which the "earliest" delayed scans (8-12 min) were considered suitable to evaluate the lesion enhancement (8,19). Moreover, these results have a remarkable technical implication because allow optimizing the scanning protocols reducing the CT acquisitions and improving the diagnosis of parotid gland lesions, especially where the biopsy is not easy to perform (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). However, we did not find a correlation between the lesion attenuation ratio of pleomorphic adenomas and the malignant tumours in our study population.…”

Section: A B Cmentioning

confidence: 64%

Delayed enhancement in differential diagnosis of salivary gland neoplasm

et al. 2019

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Background: Multi-phasic Computed Tomography (CT) evaluation allows to study the enhancement features of parotid gland masses. The aim of our study was to evaluate the role of delayed enhancement in the characterization of different histologic types of parotid tumours. Methods: Forty-eight patients (22 male and 26 female) with at least one parotid gland tumor, were included in our study. Multi-phase CT images were obtained before and 30, 120 s and 8 minutes after intravenous contrast injection. The images were evaluated by two radiologists for lesion enhancement degree. A quantitative assessment was performed using a region of interest on each lesion and density changes between different phases were compared. The tumoral enhancement ratio was calculated between the 8 minutes delayed and the early (30 s) phase. The pathological diagnosis was confirmed in all patients after surgery. Results: All patients had unilateral lesion for a total of 48 lesions. Twenty-eight were pleomorphic adenomas, 15 Warthin's tumours and 5 carcinomas. All Warthin tumours showed a rapid contrast enhancement at the early phase (30 sec) followed by a progressive wash-out during the delayed scans. Most of pleomorphic adenomas (89.2%) showed the highest density at the 8-minutes delayed phase. Malignant tumours showed slower contrast enhancement and 3 out of 5 (60%) showed a marked decrease at the 8 minutes delayed phase while the remaining 2 (40%), did not show any density reduction. The tumoral enhancement ratio was significantly different between Warthin tumours and pleomorphic adenomas and between Warthin's and malignant tumours. Conclusions: Multi-phasic CT examination with 8 minutes delayed acquisition has shown to be useful in parotid gland lesion differentiation.

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Section: A B Cmentioning

confidence: 64%

Delayed enhancement in differential diagnosis of salivary gland neoplasm

et al. 2019

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“…[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. This experimental strategy was previously used to study other Hsp90/inhibitor complexes.…”

Section: Identification Of the Hsp90 Regionr Esponsible For Molecularmentioning

confidence: 99%

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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“…The second set of compounds investigated were the 1phenyl-di(tetra)hydronaphthalene analogues (15)(16)(17)(18). Initially, the 1-phenyl-dihydronaphthalene scaffold was designed to compare placement of the phenylr ing on the 1-versus2 -position of the naphthalene ring.…”

Section: Design and Synthesis Of Novel Scaffoldsmentioning

confidence: 99%

“…[13,14] Therefore, the development of Hsp90 C-terminal inhibitors could provideaclinically useful alternative for the treatmento f cancer. [15][16][17][18][19] Studies have shown that natural product C-terminal inhibitors, [20][21][22][23][24] such as novobiocin and coumermycin A1, do not inducet he heat shock response. Unfortunately,t hese compounds manifestI C 50 values of 700 and 70 mm,r espectively.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors

Byrd

Subramanian

Sánchez

et al. 2016

Chemistry A European J

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Development of Heat shock protein 90 (Hsp90) C-terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti-proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 to 12.1 Å apart along with angles of 180°.

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Targeting the Hsp90 C-terminal domain by the chemically accessible dihydropyrimidinone scaffold

Cited by 32 publications

References 38 publications

Delayed enhancement in differential diagnosis of salivary gland neoplasm

Delayed enhancement in differential diagnosis of salivary gland neoplasm

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

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors

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