series of mold metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the heat shock protein Hsp90. In particular, bulgarialactone B was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. This compound showed high affinity for Hsp90, interacting with the 90-280 region of the N-terminal domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR. Bulgarialactone B and other natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. Preliminary results indicated in vivo activity of bulgarialactone B against an ascitic ovarian carcinoma xenograft, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.
Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors / L. Musso, S. Dallavalle, L. Merlini, A. Bava, G. Nasini, S. Penco, G. Giannini, C. Giommarelli, A. De Cesare, V. Zuco, L. Vesci, C. Pisano, F. Dal Piaz, N. De Tommasi, F. Zunino. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 18:6(2010 Aug 15), pp. 6031-6043. [10.1016/j.bmc.2010.06.068]
Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors
L. MussoPrimo
;S. DallavalleSecondo
;L. Merlini;
2010
Abstract
series of mold metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the heat shock protein Hsp90. In particular, bulgarialactone B was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. This compound showed high affinity for Hsp90, interacting with the 90-280 region of the N-terminal domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR. Bulgarialactone B and other natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. Preliminary results indicated in vivo activity of bulgarialactone B against an ascitic ovarian carcinoma xenograft, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.Pubblicazioni consigliate
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