Liphagal, a Selective Inhibitor of PI3 Kinase α Isolated from the Sponge Aka coralliphaga:  Structure Elucidation and Biomimetic Synthesis

Abstract

[structure: see text] Liphagal (1), a selective inhibitor of PI3K alpha, has been isolated from the marine sponge Aka coralliphaga collected in Dominica. The "liphagane" meroterpenoid carbon skeleton of liphagal (1) is new. A biomimetic total synthesis has been used to confirm the constitution of liphagal (1) and support a proposed biogenesis.

Total Syntheses of Liphagal: A Potent and Selective Phosphoinositide 3-Kinase α (PI3Kα) Inhibitor from the Marine Sponge Aka coralliphaga

“…Figure 1), from the marine sponge Aka coralliphaga collected from reefs in Prince Rupert Bay, Portsmouth, Dominica. 6 This marine natural product has been shown to have potent inhibitory activity against PI3Kα with an IC 50 value of 0.1 μM and tenfold greater selectivity for PI3Kα than PI3Kγ. 6 Although a large number of PI3Ks inhibitors have been reported to date, 7 liphagal, which has shown α-isoform selectivity among several isoforms, is one of the most remarkable small-molecule inhibitors.…”

“…6 This marine natural product has been shown to have potent inhibitory activity against PI3Kα with an IC 50 value of 0.1 μM and tenfold greater selectivity for PI3Kα than PI3Kγ. 6 Although a large number of PI3Ks inhibitors have been reported to date, 7 liphagal, which has shown α-isoform selectivity among several isoforms, is one of the most remarkable small-molecule inhibitors. 7a Molecular docking and molecular dynamics simulations were performed to investigate the MDA-468 (human breast): IC 50 = 1.58 μM].…”

“…7a Molecular docking and molecular dynamics simulations were performed to investigate the MDA-468 (human breast): IC 50 = 1.58 μM]. 6 Liphagal, therefore, is strongly anticipated to be a promising candidate or new lead for the development of novel molecular targeted anticancer agents. However, further biological studies of this marine natural product are severely limited by the scarcity of samples available from the sponge Aka coralliphaga (0.0019% isolated yield).…”

“…However, further biological studies of this marine natural product are severely limited by the scarcity of samples available from the sponge Aka coralliphaga (0.0019% isolated yield). 6 Structurally, liphagal possesses an unprecedented fused 6,7,5,6-tetracyclic skeleton (ABCD ring system) containing three asymmetric carbon centers (C5, C8, and C11 positions, liphagal numbering) with the characteristic feature of a highly substituted aromatic portion (D-ring). The absolute configuration of liphagal was established later by three independent research groups (i.e., the Andersen, George, and…”

“…During the period in which formula 2b was considered a possible stereostructure for siphonodictyal B, two alternative biosynthetic pathways to liphagal (1: pathways A and B in Scheme 1) were proposed by Andersen et al 6 In pathway A, the more likely biogenesis, proton-initiated polyene cyclization of farnesylated trihydroxybenzaldehyde I could produce 8-epi-siphonodictyal B (2b) following a 1,2-hydride shift from C9-H to the resulting C8 carbocation and deprotonation from C10-H. Compound 2b could then be transformed into intermediate IVb, possessing a fused 6,7-ring system, through epoxidation followed by epoxide ring opening of intermediate IIb and ring expansion (semipinacol rearrangement) of the resulting o-quinone methide IIIb.…”