Synthesis and Biological Evaluation of Several Dephosphonated Analogues of CMP-Neu5Ac as Inhibitors of GM3-Synthase

Previous studies demonstrated that reducing the GM3 content in myoblasts increased the cell resistance to hypoxic stress, suggesting that a pharmacological inhibition of the GM3 synthesis could be instrumental for the development of new treatments for ischemic diseases. Herein, the synthesis of several dephosphonated CMP‐Neu5Ac congeners and their anti‐GM3‐synthase activity is reported. Biological activity testes revealed that some inhibitors almost completely blocked the GM3‐synthase activity in vitro and reduced the GM3 content in living embryonic kidney 293A cells, eventually activating the epidermal growth factor receptor (EGFR) signaling cascade. It′s a hold up: A series of potential GM3‐synthase inhibitors was synthesized and their application was tested on living embryonic kidney 293A cells. It was found that the chemical inhibition of the GM3‐synthase activates the epidermal growth factor receptor (EGFR) signaling pathway (see figure). The investigated compounds could be useful in the development of new ways to treat ischemic diseases.