- Synthetic sulfoglycolipids targeting the serine–threonine protein kinase Akt
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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.
- 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
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- New 6-amino-6-deoxy-glycoglycerolipids derived from 2-O-β-d- glucopyranosylglycerol: Insights into the structure-activity relationship of glycoglycerolipids as anti-tumor promoters
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As part of a project aimed at obtaining compounds capable of inhibiting tumor promotion, new 6-amino-6-deoxyglycoglycerolipids (AGGLs) derived from 2-O-β-d-glucopyranosyl-sn-glycerol were synthesized and tested for their anti-tumor-promoting activity using a short-term in vitro assay of the inhibition of Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). The corresponding 6-amino-6-deoxy-β-d-octylglucosides were also prepared as simplified aminoglycolipid models and tested. Comparison with the activity of a series of previously studied glycoglycerolipids showed that replacing the 6-oxygen of the glucose moiety by a nitrogen atom greatly reduced the in vitro activity of the compounds. A two-stage mouse skin carcinogenesis test of two representative aminoglycoglycerolipids confirmed their reduced activity also in this in vivo model.
- Colombo, Diego,Gagliardi, Clarissa,Vetro, Maria,Ronchetti, Fiamma,Takasaki, Midori,Konoshima, Takao,Suzuki, Nobutaka,Tokuda, Harukuni
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