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 language | English |
|---|---|
| Pages (from-to) | 3396-3405 |
| Number of pages | 10 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 24 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - 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
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 journal › Article
}
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 -