Efficient synthesis of chloro‑derivatives of sialosyllactosylceramide, and their enhanced inhibitory effect on epidermal growth factor receptor activation

Kawashima,Nagako; Qu,Huanhuan; Lobaton,Marlin; Zhu,Zhenyuan; Sollogoub,Matthieu; Cavenee,Webster K.; Handa,Kazuko; Hakomori,Sen‑Itiroh; Zhang,Yongmin

doi:10.3892/ol.2014.1887

Efficient synthesis of chloro‑derivatives of sialosyllactosylceramide, and their enhanced inhibitory effect on epidermal growth factor receptor activation

Authors:
- Nagako Kawashima
- Huanhuan Qu
- Marlin Lobaton
- Zhenyuan Zhu
- Matthieu Sollogoub
- Webster K. Cavenee
- Kazuko Handa
- Sen‑Itiroh Hakomori
- Yongmin Zhang
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Affiliations: Division of Biomembrane Research, Pacific Northwest Research Institute, Seattle, WA 98122, USA, Institute of Paris Molecular Chemistry, University Pierre & Marie Curie Paris 6, Paris 75005, France, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA
Published online on: February 17, 2014 https://doi.org/10.3892/ol.2014.1887
Pages: 933-940

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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.

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