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Medicinal Chemistry Research

, Volume 23, Issue 11, pp 4680–4691 | Cite as

Dual and/or selective DNA-PK, PI3K inhibition and isoform selectivity of some new and known 2-amino-substituted-1,3-benzoxazines and substituted-1,3-naphthoxazines

  • Rick Morrison
  • Tyson Belz
  • Saleh K. Ihmaid
  • Jasim M. A. Al-RawiEmail author
  • Michael J. Angove
Original Research

Abstract

The 2-morpholino-substituted-benzoxazines 7a and 7b were used in the synthesis of 2-morpholino-di-O-benzyl, O-pyridin-2yl, 3-yl and 4yl-methoxy)-1,3-benzoxazines 8a–8d, and N-(2-morpholino-4-oxo-4H-benz[e][1,3]oxazin-7-yl)-N-(pyridin-2-and-3-ylmethyl)acetamides 8e and 8f. The DNA-dependent protein kinase (DNA-PK) and phosphatidylinositol 3-kinase (PI3K) α, β, γ, and δ isoforms were studied for the new compounds 8a8f and PI3K for the 18 previously synthesized compounds 926. The most active DNA-PK inhibitors were the 2-morpholino-O-substituted linear or angular naphthoxazine compounds 1820 and 2122 which showed potent and selective DNA-PK activity (IC50 from 0.01 to 2.43 µM) over PI3K. 8-(2-(4-Methylpiperazin-1-yl)ethoxy)-2-morpholino compound 13, and 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy) compound 25 showed selective DNA-PK inhibition. 2-morpholino-8-substituted-benzoxazine 9 (8-ph) and 1012 (8-(pyridine-2-, 3-, or 4-ylmethoxy) showed high-to-moderate inhibition of PI3K and DNA-PK. A similar pattern for DNA-PK nonselectivity over PI3K was observed for compounds with 7,8-O-bis-substituted 8a, 8c, and 8d. No DNA-PK selectivity over PI3K was observed regardless whether the substitution was phenyl, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, and pyridin-4-ylmethoxy.

Keywords

Synthesis 2-Amino-substituted-1,3-benzoxazines 2-Amino-naphthoxazines DNA-PK PI3K isoform inhibition and selectivity 

Supplementary material

44_2014_1037_MOESM1_ESM.pdf (844 kb)
Supplementary material 1 (PDF 844 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Rick Morrison
    • 1
  • Tyson Belz
    • 1
  • Saleh K. Ihmaid
    • 1
  • Jasim M. A. Al-Rawi
    • 1
    Email author
  • Michael J. Angove
    • 1
  1. 1.School of Pharmacy and Applied ScienceLa Trobe UniversityBendigoAustralia

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