Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt

Barbara Costa, Milind Dangate, Maria Vetro, Giulia Donvito, Luca Gabrielli, Loredana Amigoni, Giuliana Cassinelli, Cinzia Lanzi, Michela Ceriani, Luca De Gioia, Giulia Filippi, Laura Cipolla, Nadia Zaffaroni, Paola Perego, Diego Colombo

Research output: Contribution to journalArticle

Abstract

The serine–threonine protein kinase Akt, also known as protein kinase B, is a key component of the phosphoinositide 3-kinase (PI3K)–Akt–mTOR axis. Deregulated activation of this pathway is frequent in human tumors and Akt-dependent signaling appears to be critical in cell survival. PI3K activation generates 3-phosphorylated phosphatidylinositols that bind Akt pleckstrin homology (PH) domain. The blockage of Akt PH domain/phosphoinositides interaction represents a promising approach to interfere with the oncogenic potential of over-activated Akt. In the present study, phosphatidyl inositol mimics based on a β-glucoside scaffold have been synthesized as Akt inhibitors. The compounds possessed one or two lipophilic moieties of different length at the anomeric position of glucose, and an acidic or basic group at C-6. Docking studies, ELISA Akt inhibition assays, and cellular assays on different cell models highlighted 1-O-octadecanoyl-2-O-β-D-sulfoquinovopyranosyl-sn-glycerol as the best Akt inhibitor among the synthesized compounds, which could be considered as a lead for further optimization in the design of Akt inhibitors.

Original languageEnglish
Pages (from-to)3396-3405
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number16
DOIs
Publication statusPublished - Aug 15 2016

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Keywords

  • Akt
  • Cancer
  • Inhibitors
  • Phosphatidyl inositol analogues
  • Sulfoquinovose

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Costa, B., Dangate, M., Vetro, M., Donvito, G., Gabrielli, L., Amigoni, L., Cassinelli, G., Lanzi, C., Ceriani, M., De Gioia, L., Filippi, G., Cipolla, L., Zaffaroni, N., Perego, P., & Colombo, D. (2016). Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt. Bioorganic and Medicinal Chemistry, 24(16), 3396-3405. https://doi.org/10.1016/j.bmc.2016.05.031