Synthesis of phosphatidylinositol 3-kinase (PI3K) inhibitory analogues of the sponge meroterpenoid liphagal

Alban R Pereira; Wendy K Strangman; Frederic Marion; Larry Feldberg; Deborah Roll; Robert Mallon; Irwin Hollander; Raymond J Andersen

doi:10.1021/jm100531u

Synthesis of phosphatidylinositol 3-kinase (PI3K) inhibitory analogues of the sponge meroterpenoid liphagal

J Med Chem. 2010 Dec 23;53(24):8523-33. doi: 10.1021/jm100531u. Epub 2010 Dec 1.

Authors

Alban R Pereira¹, Wendy K Strangman, Frederic Marion, Larry Feldberg, Deborah Roll, Robert Mallon, Irwin Hollander, Raymond J Andersen

Affiliation

¹ Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.

PMID: 21121631
DOI: 10.1021/jm100531u

Abstract

Analogues of the sponge meroterpenoid liphagal 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drug Stability
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / chemistry
Phosphatidylinositol 3-Kinase / chemistry
Phosphoinositide-3 Kinase Inhibitors*
Porifera*
Stereoisomerism
Structure-Activity Relationship
Terpenes / chemical synthesis*
Terpenes / chemistry

Substances

Isoenzymes
Phosphoinositide-3 Kinase Inhibitors
Terpenes
liphagal
Phosphatidylinositol 3-Kinase