کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1359073 | 981380 | 2010 | 13 صفحه PDF | دانلود رایگان |
A 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.
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Journal: Bioorganic & Medicinal Chemistry - Volume 18, Issue 16, 15 August 2010, Pages 6031–6043