Synthesis of N-oxyamide analogues of protein kinase B (Akt) targeting anionic glycoglycerolipids and their antiproliferative activity on human ovarian carcinoma cells?

Organic & Biomolecular Chemistry Pub Date: 2023-07-26 DOI: 10.1039/D3OB00891F

Abstract

N-Oxyamides of bioactive anionic glycoglycerolipids based on 2-O-β-D-glucosylglycerol were efficiently prepared. However, the oxidation step of the primary hydroxyl group of the glucose moiety in the presence of the N-oxyamide function appeared to be a difficult task that was nevertheless conveniently achieved for the first time by employing a chemoenzymatic laccase/TEMPO procedure. The obtained N-oxyamides exhibited a higher inhibition of proliferation of ovarian carcinoma IGROV-1 cells in serum-free medium than in complete medium, similarly to the corresponding bioactive esters. Stability and serum binding studies indicated that the observed reduced activity of the compounds in complete medium could be mainly due to a binding effect of serum proteins rather than the hydrolytic degradation of glycoglycerolipid acyl chains. Furthermore, the results of the cellular studies under serum-free conditions suggested that the N-oxyamide group could increase the antiproliferative activity of a glycoglycerolipid independently of the presence of the anionic carboxylic group. Cellular studies in other cell lines besides IGROV-1 also support a certain degree of selectivity of this series of compounds for tumor cells with Akt hyperactivation.

Graphical abstract: Synthesis of N-oxyamide analogues of protein kinase B (Akt) targeting anionic glycoglycerolipids and their antiproliferative activity on human ovarian carcinoma cells
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