Inhibition of Phosphatidylinositol-3-kinase by the Furanosesquiterpenoid Hibiscone C and its Derivatives

Furanosteroids like Wortmannin are proven to inhibit the continuation of the phosphatidylinositol-3-kinase (PI-3K) pathway. This pathway is upregulated in highly proliferative cells, such as cancer cells. Although it is able to effectively inhibit the PI-3K pathway, Wortmannin has off-target effects, is unstable in neutral pHs, and needs a time-consuming chemical synthesis, all of which prevents it from being considered as a chemotherapeutic drug. Recently published work from this lab showed that Hibiscone C, a structurally similar furanosteroid, has the ability to inhibit PI-3K. Using activated T-cells which are known to upregulate the PI-3K pathway, the ability of Hibiscone C derivatives to inhibit the PI-3K pathway were tested and the requirements of the carbonyls in the inhibitor necessary to inhibit the pathway were investigated. The hydrolyzation of the left carbonyl proved to prevent inhibition of the PI-3K pathway while the hydrolyzation of the right carbonyl still allowed for inhibition. The results of this research will direct future synthesis projects to create a more specific, stable, and potent inhibitor of the PI-3K pathway