We have recently reported that allosteric modulation of the chaperone protein Hsp901 can be achieved in an allosteric fashion using a family of 2-phenyl-benzofuran derivatives that target an allosteric pocket at the C-terminal domain of the protein.2,3 These ligands are mainly activators of the chaperone ATPase activity3 and are accelerators of the protein internal dynamics.4 As a result, they tune Hsp90 chaperone activity in ways that we are just beginning to unravel. We are going to present the synthetic approaches towards an expanded library of about 40 benzofuran derivatives diversified at positions R1 and R2 along with the interaction studies with full length Hsp905 and the effects on Hsp90 enzymatic and chaperoning activity. Figure 1: 2-phenyl-benzofuran diversification at positions R1 and R2 (top) and docked complex of Hsc82 (Hsp90 yeast form) with one of our derivatives (bottom). 1. Jackson, S. E. In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg: 2013; Vol. 328, p 155. 2. Morelli, L.; Bernardi, A.; Sattin, S. Carbohydr Res 2014, 390C, 33. 3. Sattin, S.; Tao, J.; Vettoretti, G.; Moroni, E.; Pennati, M.; Lopergolo, A.; Morelli, L.; Bugatti, A.; Zuehlke, A.; Moses, M.; Prince, T.; Kijima, T.; Beebe, K.; Rusnati, M.; Neckers, L.; Zaffaroni, N.; Agard, D. A.; Bernardi, A.; Colombo, G. Chem. Eur. J. 2015, 21, 13598. 4. Vettoretti, G.; Moroni, E.; Sattin, S.; Tao, J.; Agard, D. A.; Bernardi, A.; Colombo, G. Sci Rep 2016, 6, 23830. 5. Sattin, S.; Panza, M.; Vasile, F.; Berni, F.; Goti, G.; Tao, J.; Moroni, E.; Agard, D.; Colombo, G.; Bernardi, A. Eur. J. Org. Chem. 2016, DOI: 10.1002/ejoc.201600420.

Benzofuran Derivatives Activators of the Chaperone Protein Hsp90: Synthesis, Interaction Studies and Biological Effects / S. Sattin, J. Tao, F. Vasile, E. Moroni, D.A. Agard, A. Bernardi, G. Colombo. ((Intervento presentato al convegno Ischia Advanced School of Organic Chemistry (IASOC 2016) tenutosi a Ischia nel 2016.

Benzofuran Derivatives Activators of the Chaperone Protein Hsp90: Synthesis, Interaction Studies and Biological Effects

S. Sattin
Primo
;
F. Vasile;A. Bernardi
Penultimo
;
2016-09

Abstract

We have recently reported that allosteric modulation of the chaperone protein Hsp901 can be achieved in an allosteric fashion using a family of 2-phenyl-benzofuran derivatives that target an allosteric pocket at the C-terminal domain of the protein.2,3 These ligands are mainly activators of the chaperone ATPase activity3 and are accelerators of the protein internal dynamics.4 As a result, they tune Hsp90 chaperone activity in ways that we are just beginning to unravel. We are going to present the synthetic approaches towards an expanded library of about 40 benzofuran derivatives diversified at positions R1 and R2 along with the interaction studies with full length Hsp905 and the effects on Hsp90 enzymatic and chaperoning activity. Figure 1: 2-phenyl-benzofuran diversification at positions R1 and R2 (top) and docked complex of Hsc82 (Hsp90 yeast form) with one of our derivatives (bottom). 1. Jackson, S. E. In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg: 2013; Vol. 328, p 155. 2. Morelli, L.; Bernardi, A.; Sattin, S. Carbohydr Res 2014, 390C, 33. 3. Sattin, S.; Tao, J.; Vettoretti, G.; Moroni, E.; Pennati, M.; Lopergolo, A.; Morelli, L.; Bugatti, A.; Zuehlke, A.; Moses, M.; Prince, T.; Kijima, T.; Beebe, K.; Rusnati, M.; Neckers, L.; Zaffaroni, N.; Agard, D. A.; Bernardi, A.; Colombo, G. Chem. Eur. J. 2015, 21, 13598. 4. Vettoretti, G.; Moroni, E.; Sattin, S.; Tao, J.; Agard, D. A.; Bernardi, A.; Colombo, G. Sci Rep 2016, 6, 23830. 5. Sattin, S.; Panza, M.; Vasile, F.; Berni, F.; Goti, G.; Tao, J.; Moroni, E.; Agard, D.; Colombo, G.; Bernardi, A. Eur. J. Org. Chem. 2016, DOI: 10.1002/ejoc.201600420.
Settore CHIM/06 - Chimica Organica
http://www.iasoc.it/home/
Benzofuran Derivatives Activators of the Chaperone Protein Hsp90: Synthesis, Interaction Studies and Biological Effects / S. Sattin, J. Tao, F. Vasile, E. Moroni, D.A. Agard, A. Bernardi, G. Colombo. ((Intervento presentato al convegno Ischia Advanced School of Organic Chemistry (IASOC 2016) tenutosi a Ischia nel 2016.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/481210
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