Inositol glycans (IGs) are naturally occurring oligosaccharides that can stimulate insulin-sensitive cells. Several synthetic IG analogues have been shown to activate the insulin signaling pathway, resulting in metabolic changes including the stimulation of pyruvate dehydrogenase (PDH) phosphatase that can further stimulate aerobic metabolism in cells. Cancer cells shift to anaerobic metabolism (Warburg Effect) in part to escape mitochondria-based intrinsic apoptosis. So, a strategy to control cancerous growth might be to stimulate aerobic metabolism in cancer cells and reverse the Warburg effect. The IG's ability to stimulate aerobic metabolism could force cancer cells to restore normal citric acid cycle and oxidative phosphorylation in mitochondria, possibly leading to the induction of intrinsic apoptosis.A lipid-linked IG analogue, GlcN-(a1-6)-myo-Inos-2-palmitate, IG-1  , has been previously shown to be selectively cytotoxic towards a variety of cultured human cancer cell lines as well as in vivo in a murine cancer model. Its medicinal utility, however, is limited by its instability under physiological conditions due to the presence of a hydrolyzable ester linkage in the molecule. To overcome this limitation, a non-hydrolyzable ether-linked analogue, IG-1E  , has been synthesized and evaluated for cytotoxicity towards cancer cells. Preliminary data show promising selective cytotoxicity of IG-1E  towards cultured human cancer cell lines. A series of non-hydrolyzable, lipid-linked IG analogues with varying lipid chain length have also been synthesized and evaluated for cytotoxicity toward cancer cells. Synthesis and comparative biological activity of these novel anti-cancer small molecules will be summarized in this presentation.

Synthesis of non-hydrolyzable, lipid-linked inositol glycans with selective anti-cancer activity

243rd National Meeting (2012)

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