title: Synthesis of linear and angular aryl-morpholino-naphth-oxazines, their DNA-PK, PI3K, PDE3A and antiplatelet activity.
abstract: To continue our study of 2-morpholino-benzoxazine based compounds, which show useful activity against PI3K family enzymes or antiplatelet activity, we designed and synthesized a series of linear 6.7-fused, 5,6-angular fused and 7,8-angular fused-aryl-morpholino-naphth-oxazines. The compounds were prepared from substituted 2-hydroxynaphthoic acid to give the corresponding thioxo analogues 8, 9, 15 and 19. The thioxo products were then converted to the morpholino substituted analogue. The aryl group was introduced by Suzuki coupling of bromo precursors. The products were evaluated for activity at PI3K family enzymes and as platelet aggregation inhibitors and compared to reported unsubstituted analogues. The linear 6.7-fused product 13a and 13b were moderated potent but selective PI3Kδ isoform inhibitors (IC50=7.7 and 5.61μM). Good antiplatelet activity was noticed for the angular 7,8-fused compounds 22a, b, k and l with IC50=3.0,14.0, 2.0 and 5.0μM respectively. The antiplatelet activity is independent of PDE3.
authors.affiliation: Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, PO Box 199, Bendigo, VIC 3552, Australia. Electronic address: rmmorrison@students.latrobe.edu.au.
authors.forename: Rick
authors.initials: R
authors.lastname: Morrison
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: joyce.zheng@monash.edu.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: Ian.Jennings@monash.edu.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Jennings
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: Philip.Thompson@monash.edu.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
authors.affiliation: Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, PO Box 199, Bendigo, VIC 3552, Australia. Electronic address: j.al-rawi@latrobe.edu.au.
authors.forename: Jasim M A
authors.initials: JMA
authors.lastname: Al-Rawi
mesh_terms: D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D060172:Morpholinos / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D048588:Benzoxazines; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D051747:DNA-Activated Protein Kinase; D060172:Morpholinos; D019869:Phosphatidylinositol 3-Kinases; D058987:Phosphodiesterase 3 Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors; C517287:PDE3A protein, human
keywords: 5,6-Angular fused and 7,8-angular fused-aryl-morpholino-naphth-oxazines; 6.7-Fused; DNA-PK; PDE3A antiplatelet activity; PI3K