title: Preparation and evaluation of trisubstituted pyrimidines as phosphatidylinositol 3-kinase inhibitors. 3-Hydroxyphenol analogues and bioisosteric replacements.
abstract: Two classes of trisubstituted pyrimidines related to PI-103 1 have been prepared and their inhibitory activities against phosphatidylinositol 3-kinase (PI3K) p110α were determined. From those with direct 6-aryl substitution compound 11a was the most potent inhibitor with an IC₅₀ value of 62 nM, and showed similar activity against other class 1a PI3K isoforms tested, p110β and p110γ. When a linking chain was introduced, as in the second exemplified class, compound 15f inhibited p110α with IC₅₀ 142 nM, and showed greater selectivity towards p110α. Compounds of both classes showed promising inhibition of cellular proliferation in IGROV-1 ovarian cancer cells. Among compounds designed to replace the 3-phenolic motif with structural isosteres, analogues incorporating a 4-indazolyl group possessed enzyme and cellular activities comparable to the parent phenols.
authors.affiliation: The Institute of Cancer Research, Belmont, Surrey, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Large
authors.forename: Jane E
authors.initials: JE
authors.lastname: Torr
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Francesca di
authors.initials: Fd
authors.lastname: Stefano
authors.forename: Frederique
authors.initials: F
authors.lastname: Urban
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Shuttleworth
authors.forename: Nahid
authors.initials: N
authors.lastname: Saghir
authors.forename: Peter
authors.initials: P
authors.lastname: Sheldrake
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
mesh_terms: D000818:Animals; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C557919:3-(2-morpholino-6-(2-(pyridin-4-yl)ethylamino)pyrimidin-4-yl)phenol; C557918:3-(4-morpholino-6-(pyridin-2-yl)pyrimidin-2-yl)phenol; D009025:Morpholines; D010636:Phenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058539:Phosphatidylinositol 3-Kinase