Synthesis of Phosphatidylinositol 3-Kinase (PI3K) Inhibitory Analogues of the Sponge Meroterpenoid Liphagal

Analogues of the sponge meroterpenoid liphagal (1) have been synthesized and evaluated for inhibition of PI3Kα and PI3Kγ as part of a program aimed at developing new isoform-selective PI3K inhibitors. One of the analogues, compound 24, with IC50 values of 66 nM against PI3Kα and 1840 nM against PI3Kγ, representing a 27-fold preference for PI3Kα, exhibited enhanced chemical stability and modestly enhanced potency and selectivity compared with the natural product liphagal (1).