1609691-02-2Relevant articles and documents
Synthesis of potential allosteric modulators of Hsp90 by chemical glycosylation of Eupomatenoid-6
Morelli, Laura,Bernardi, Anna,Sattin, Sara
, p. 33 - 41 (2014/04/17)
Hsp90 (Heat shock protein-90) is a chaperone protein and an established anti-apoptotic target in cancer therapy. Most of the known small-molecule inhibitors that have shown potent antitumor activity target the Hsp90 N-terminal domain and directly inhibit its ATP-ase activity. Many of these molecules display important secondary effects. A different approach to Hsp90 inhibition consists of targeting the protein C-terminal domain (CTD) and modulating its chaperone activity through allosteric effects. Using an original computational approach, allosteric hot-spots in the CTD have been recently identified that control interdomain communication. A combination of virtual and experimental screening enabled identification of a rhamnosylated benzofuran (Eupomatenoid-2) as a lead for further development. In this paper we describe glycodiversification of Eupomatenoid-2 using chemical glycosylation of the 2-(4′-hydroxyphenyl)benzofuran aglycon (a.k.a. Eupomatenoid-6). Glycosylation of the phenol by glycosyl bromides under basic conditions afforded the desired products in the gluco-, galacto-, and fuco-series. This approach failed in the manno- and rhamno-series. However, mannosylation and rhamnosylation of Eupomatenoid-6 could be obtained under carefully controlled acidic conditions, using O-benzoxazolyl imidate (OBox) donors. The glycosides obtained are currently under investigation as modulators of Hsp90 chaperone activity.
