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Dal Piaz F.,University of Salerno | Malafronte N.,University of Salerno | Romano A.,University of Salerno | Gallotta D.,University of Salerno | And 6 more authors.
Phytochemistry | Year: 2012

Investigation of roots extracts Pseudrocedrela kotschyi and Trichilia emetica led to identification of 5 limonoid derivatives, Kotschyins D-H, and 11 known compounds. Their structures were elucidated by extensive 1D and 2D NMR experiments in conjunction with mass spectrometry. A surface plasmon resonance (SPR) approach was adopted to screen their Hsp90 binding capability and kotschyin D showed a significant affinity for the chaperone. Therefore, the characterization of the biological activity of kotschyin D by means of a panel of chemical and biological approaches, including limited proteolysis, molecular docking and biochemical and cellular assays, was performed. Our result indicated this compound as a type of client selective Hsp90 inhibitor, directly binding to the middle domain of the protein and possibly preventing its interaction with the activator of Hsp90 ATPase 1 (Aha1). © 2011 Elsevier Ltd. All rights reserved.


Piaz F.D.,University of Salerno | Vassallo A.,University of Basilicata | Temraz A.,Al - Azhar University of Egypt | Cotugno R.,University of Salerno | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2013

The potential of heat shock protein 90 (Hsp90) as a therapeutic target for numerous diseases has made the identification and optimization of novel Hsp90 inhibitors an emerging therapeutic strategy. A surface plasmon resonance (SPR) approach was adopted to screen some iridoids for their Hsp90 α binding capability. Twenty-four iridoid derivatives, including 13 new natural compounds, were isolated from the leaves of Tabebuia argentea and petioles of Catalpa bignonioides. Their structures were elucidated by NMR, electrospray ionization mass spectrometry, and chemical methods. By means of a panel of chemical and biological approaches, four iridoids were demonstrated to bind Hsp90 α. In particular, the dimeric iridoid argenteoside A was shown to efficiently inhibit the chaperone in biochemical and cellular assays. Our results disclose C 9-type iridoids as a novel class of Hsp90 inhibitors. © 2013 American Chemical Society.


Hanessian S.,University of Montréal | Auzzas L.,University of Montréal | Auzzas L.,CNR Institute of Biomolecular Chemistry | Larsson A.,University of Montréal | And 6 more authors.
ACS Medicinal Chemistry Letters | Year: 2010

The inhibitory activity of an ?-alkoxy analogue of the HDAC inhibitor, Vorinostat (SAHA), against the 11 isoforms of HDAC is described and evaluated with regard to structural biology information retrieved through computational methods. Preliminary absorption and metabolism studies were performed, which positioned this compound as a potential candidate for further preclinical studies and delineated measures for improving its pharmacokinetic profile. © 2010 American Chemical Society.


Auzzas L.,University of Montréal | Auzzas L.,CNR Institute of Biomolecular Chemistry | Larsson A.,University of Montréal | Larsson A.,Umeå University | And 11 more authors.
Journal of Medicinal Chemistry | Year: 2010

Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors. © 2010 American Chemical Society.

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