title: Synthesis of potential allosteric modulators of Hsp90 by chemical glycosylation of Eupomatenoid-6.
abstract: 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.
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Morelli
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bernardi
authors.affiliation: Università degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133 Milano, Italy. Electronic address: sara.sattin@unimi.it.
authors.forename: Sara
authors.initials: S
authors.lastname: Sattin
keywords: Eupomatenoid; Glycodiversification; Hsp90; O-Benzoxazolyl imidate (OBox); Phase Transfer Catalysis; Phenol glycosylation