Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines

S. Ihmaid, J. Al-Rawi, C. Bradley, M. J. Angove, M. N. Robertson, R. L. Clark

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 9-0-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 mu M, 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 mu M, 24 IC(50) = 0.191 mu M, and 22 IC(50) = 0.331 mu M.

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.
LanguageEnglish
Pages3983-3994
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number13
DOIs
Publication statusPublished - 1 Jul 2011

Fingerprint

Oxazines
DNA-Activated Protein Kinase
Morpholinos
Platelets
Blood Platelets
Structure-Activity Relationship
Phosphatidylinositol 3-Kinases
Platelet Aggregation
Collagen
Agglomeration
X-Rays
X rays
oxazine 1

Keywords

  • dependent protein-kinase
  • anti-platelet activity
  • potent
  • identification
  • DNA-PK IC50
  • autophosphorylation
  • docking
  • morpholino-1,3-naphth-oxazine
  • catalytic subunit
  • LY294002
  • structural elucidation
  • homology modelling
  • morpholino-substituted-1,3-naphth-oxazines

Cite this

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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 9-0-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 mu M, 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 mu M, 24 IC(50) = 0.191 mu M, and 22 IC(50) = 0.331 mu M. 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.",
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Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines. / Ihmaid, S.; Al-Rawi, J.; Bradley, C.; Angove, M. J.; Robertson, M. N.; Clark, R. L.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 13, 01.07.2011, p. 3983-3994.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines

AU - Ihmaid, S.

AU - Al-Rawi, J.

AU - Bradley, C.

AU - Angove, M. J.

AU - Robertson, M. N.

AU - Clark, R. L.

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AB - 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 9-0-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 mu M, 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 mu M, 24 IC(50) = 0.191 mu M, and 22 IC(50) = 0.331 mu M. 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.

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KW - docking

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KW - catalytic subunit

KW - LY294002

KW - structural elucidation

KW - homology modelling

KW - morpholino-substituted-1,3-naphth-oxazines

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