title: Regioselective synthesis of 5- and 6-methoxybenzimidazole-1,3,5-triazines as inhibitors of phosphoinositide 3-kinase.
abstract: Phosphoinositide 3-kinases (PI3K) hold significant therapeutic potential as novel targets for the treatment of cancer. ZSTK474 (4a) is a potent, pan-PI3K inhibitor currently under clinical evaluation for the treatment of cancer. Structural studies have shown that derivatisation at the 5- or 6-position of the benzimidazole ring may influence potency and isoform selectivity. However, synthesis of these derivatives by the traditional route results in a mixture of the two regioisomers. We have developed a straightforward regioselective synthesis that gave convenient access to 5- and 6-methoxysubstituted benzimidazole derivatives of ZSTK474. While 5-methoxy substitution abolished activity at all isoforms, the 6-methoxy substitution is consistently 10-fold more potent. This synthesis will allow convenient access to further 6-position derivatives, thus allowing the full scope of the structure-activity relationships of ZSTK474 to be probed.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, 381 Royal Pde, Parkville, Victoria 3052, Australia.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Miller
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Pinson
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Zheng
authors.forename: Ian G
authors.initials: IG
authors.lastname: Jennings
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009574:Nitro Compounds / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D009574:Nitro Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014227:Triazines; C510150:ZSTK474; C060569:2-methoxy-5-methyl-4-nitroaniline