title: Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines.
abstract: A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55±4 and 85±4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC(50)=0.091 μM, 24 IC(50)=0.191 μM, and 22 IC(50)=0.331 μM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity.
authors.affiliation: School of Pharmacy and Applied Science, La Trobe University, Bendigo, Australia. sihmaid@students.latrobe.edu.au
authors.forename: Saleh
authors.initials: S
authors.lastname: Ihmaid
authors.forename: Jasim
authors.initials: J
authors.lastname: Al-Rawi
authors.forename: Christopher
authors.initials: C
authors.lastname: Bradley
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Angove
authors.forename: Murray N
authors.initials: MN
authors.lastname: Robertson
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Clark
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003094:Collagen / Q000494:pharmacology; D003198:Computer Simulation; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: C561757:2-morpholin-7-(pyridin-2-ylmethoxy)-4H-naphth(2,1-e)-1,3-oxazin-4-one; D009025:Morpholines; D010078:Oxazines; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors; C037574:morpholine; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D051747:DNA-Activated Protein Kinase