Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors

Bioorganic & Medicinal Chemistry
Loana MussoFranco Zunino

Abstract

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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Citations

Aug 24, 2010·Applied Microbiology and Biotechnology·Yunquan ZhengYanghao Guo
Feb 15, 2012·ACS Combinatorial Science·Mathieu AchardJohn A Porco
Apr 16, 2013·Chemical Reviews·Jin-Ming GaoJian-Chun Qin
Mar 9, 2012·Expert Opinion on Drug Discovery·Hardik J PatelTony Taldone
Dec 8, 2015·Journal of Natural Products·Andrea A StierleHakim Djaballah
Feb 22, 2012·Clinics in Laboratory Medicine·Panga Jaipal ReddySanjeeva Srivastava
Jul 28, 2012·Chemical Biology & Drug Design·Long LinGuang-Fu Yang
May 25, 2018·Natural Product Research·Xiao-Hua LiYun Deng
Sep 22, 2020·Beilstein Journal of Organic Chemistry·Ken-Ichi NakashimaMakoto Inoue
Mar 31, 2015·ACS Chemical Neuroscience·Smita R ParanjapeT Chris Gamblin

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