Synthesis of phosphatidylinositol 3-kinase (PI3K) inhibitory analogues of the sponge meroterpenoid liphagal.
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.
Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada.
Alban R
AR
Pereira
Wendy K
WK
Strangman
Frederic
F
Marion
Larry
L
Feldberg
Deborah
D
Roll
Robert
R
Mallon
Irwin
I
Hollander
Raymond J
RJ
Andersen
D000818:Animals; D004355:Drug Stability; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011161:Porifera; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000138:chemical synthesis* / Q000737:chemistry
D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013729:Terpenes; C513880:liphagal; D058539:Phosphatidylinositol 3-Kinase