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

5 Citations (Scopus)

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

Fingerprint

Phosphatidylinositols
Protein Kinases
1-Phosphatidylinositol 4-Kinase
Proto-Oncogene Proteins c-akt
Glucosides
Assays
Phosphotransferases
Glycerol
Chemical activation
Cell Survival
Enzyme-Linked Immunosorbent Assay
Glucose
Scaffolds
Tumors
Cells
sulfoglycolipids
Neoplasms
Pleckstrin Homology Domains
platelet protein P47

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., ... 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

Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt. / Costa, Barbara; Dangate, Milind; Vetro, Maria; Donvito, Giulia; Gabrielli, Luca; Amigoni, Loredana; Cassinelli, Giuliana; Lanzi, Cinzia; Ceriani, Michela; De Gioia, Luca; Filippi, Giulia; Cipolla, Laura; Zaffaroni, Nadia; Perego, Paola; Colombo, Diego.

In: Bioorganic and Medicinal Chemistry, Vol. 24, No. 16, 15.08.2016, p. 3396-3405.

Research output: Contribution to journalArticle

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, vol. 24, no. 16, pp. 3396-3405. https://doi.org/10.1016/j.bmc.2016.05.031
Costa B, Dangate M, Vetro M, Donvito G, Gabrielli L, Amigoni L et al. Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt. Bioorganic and Medicinal Chemistry. 2016 Aug 15;24(16):3396-3405. https://doi.org/10.1016/j.bmc.2016.05.031
Costa, Barbara ; Dangate, Milind ; Vetro, Maria ; Donvito, Giulia ; Gabrielli, Luca ; Amigoni, Loredana ; Cassinelli, Giuliana ; Lanzi, Cinzia ; Ceriani, Michela ; De Gioia, Luca ; Filippi, Giulia ; Cipolla, Laura ; Zaffaroni, Nadia ; Perego, Paola ; Colombo, Diego. / Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt. In: Bioorganic and Medicinal Chemistry. 2016 ; Vol. 24, No. 16. pp. 3396-3405.
@article{3863bd03e1934675b1fa5bbb8ee0fde8,
title = "Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt",
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.",
keywords = "Akt, Cancer, Inhibitors, Phosphatidyl inositol analogues, Sulfoquinovose",
author = "Barbara Costa and Milind Dangate and Maria Vetro and Giulia Donvito and Luca Gabrielli and Loredana Amigoni and Giuliana Cassinelli and Cinzia Lanzi and Michela Ceriani and {De Gioia}, Luca and Giulia Filippi and Laura Cipolla and Nadia Zaffaroni and Paola Perego and Diego Colombo",
year = "2016",
month = "8",
day = "15",
doi = "10.1016/j.bmc.2016.05.031",
language = "English",
volume = "24",
pages = "3396--3405",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "16",

}

TY - JOUR

T1 - Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt

AU - Costa, Barbara

AU - Dangate, Milind

AU - Vetro, Maria

AU - Donvito, Giulia

AU - Gabrielli, Luca

AU - Amigoni, Loredana

AU - Cassinelli, Giuliana

AU - Lanzi, Cinzia

AU - Ceriani, Michela

AU - De Gioia, Luca

AU - Filippi, Giulia

AU - Cipolla, Laura

AU - Zaffaroni, Nadia

AU - Perego, Paola

AU - Colombo, Diego

PY - 2016/8/15

Y1 - 2016/8/15

N2 - 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.

AB - 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.

KW - Akt

KW - Cancer

KW - Inhibitors

KW - Phosphatidyl inositol analogues

KW - Sulfoquinovose

UR - http://www.scopus.com/inward/record.url?scp=84978296066&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978296066&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2016.05.031

DO - 10.1016/j.bmc.2016.05.031

M3 - Article

VL - 24

SP - 3396

EP - 3405

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 16

ER -