title: Efficient synthesis of chloro-derivatives of sialosyllactosylceramide, and their enhanced inhibitory effect on epidermal growth factor receptor activation.
abstract: Glycosphingolipids are components of essentially all mammalian cell membranes and are involved in a variety of significant cellular functions, including proliferation, adhesion, motility and differentiation. Sialosyllactosylceramide (GM3) is known to inhibit the activation of epidermal growth factor receptor (EGFR). In the present study, an efficient method for the total chemical synthesis of monochloro- and dichloro-derivatives of the sialosyl residue of GM3 was developed. The structures of the synthesized compounds were fully characterized by high-resolution mass spectrometry and nuclear magnetic resonance. In analyses of EGFR autophosphorylation and cell proliferation ([3H]-thymidine incorporation) in human epidermoid carcinoma A431 cells, two chloro-derivatives exhibited stronger inhibitory effects than GM3 on EGFR activity. Monochloro-GM3, but not GM3 or dichloro-GM3, showed a significant inhibitory effect on ΔEGFR, a splicing variant of EGFR that lacks exons 2-7 and is often found in human glioblastomas. The chemical synthesis of other GM3 derivatives using approaches similar to those described in the present study, has the potential to create more potent EGFR inhibitors to block cell growth or motility of a variety of types of cancer that express either wild-type EGFR or ΔEGFR.
authors.affiliation: Division of Biomembrane Research, Pacific Northwest Research Institute, Seattle, WA 98122, USA.
authors.forename: Nagako
authors.initials: N
authors.lastname: Kawashima
authors.affiliation: Institute of Paris Molecular Chemistry, University Pierre & Marie Curie Paris 6, Paris 75005, France ; Glycochemistry and Glycobiology Lab, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Pudong, Shanghai 201203, P.R. China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Qu
authors.affiliation: Division of Biomembrane Research, Pacific Northwest Research Institute, Seattle, WA 98122, USA.
authors.forename: Marlin
authors.initials: M
authors.lastname: Lobaton
authors.affiliation: Institute of Paris Molecular Chemistry, University Pierre & Marie Curie Paris 6, Paris 75005, France.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Institute of Paris Molecular Chemistry, University Pierre & Marie Curie Paris 6, Paris 75005, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sollogoub
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: Division of Biomembrane Research, Pacific Northwest Research Institute, Seattle, WA 98122, USA.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Handa
authors.affiliation: Division of Biomembrane Research, Pacific Northwest Research Institute, Seattle, WA 98122, USA ; Departments of Pathobiology and Global Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sen-Itiroh
authors.initials: SI
authors.lastname: Hakomori
authors.affiliation: Institute of Paris Molecular Chemistry, University Pierre & Marie Curie Paris 6, Paris 75005, France ; Institute for Interdisciplinary Research, Jianghan University, Wuhan Economic and Technological Development Zone, Wuhan, Hubei 430056, P.R. China.
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Zhang
keywords: EGFR activation; EGFR inhibitors; GM3; cell proliferation; chloro-derivatives of GM3; glycosphingolipids