2. Academic Validation
  3. Synthesis, structure elucidation, DNA-PK and PI3K and anti-cancer activity of 8- and 6-aryl-substituted-1-3-benzoxazines

Synthesis, structure elucidation, DNA-PK and PI3K and anti-cancer activity of 8- and 6-aryl-substituted-1-3-benzoxazines

  • Eur J Med Chem. 2016 Mar 3;110:326-39. doi: 10.1016/j.ejmech.2016.01.042.
Rick Morrison 1,  Jasim M A Al-Rawi 2,  Ian G Jennings 3,  Philip E Thompson 4,  Michael J Angove 5
Affiliations

Affiliations

  • 1 Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia. Electronic address: [email protected].
  • 2 Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia. Electronic address: [email protected].
  • 3 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: [email protected].
  • 4 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: [email protected].
  • 5 Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia. Electronic address: [email protected].
PMID: 26854431 DOI: 10.1016/j.ejmech.2016.01.042
Abstract

The synthesis of 6-aryl, 8- aryl, and 8-aryl-6-chloro-2-morpholino-1,3-benzoxazines with potent activity against PI3K and DNA-PK is described. Synthesis of thirty one analogues was facilitated by an improved synthesis of 3-bromo-2-hydroxybenzoic acid 13 by de-sulphonation of 3-bromo-2-hydroxy-5-sulfobenzoic acid 12 en route to 2-methylthio-substituted-benzoxazine intermediates 17-19. From this series, compound 20k (LTURM34) (dibenzo[b,d]thiophen-4-yl) (IC50 = 0.034 μM) was identified as a specific DNA-PK Inhibitor, 170 fold more selective for DNA-PK activity compared to PI3K activity. Other compounds of the series show markedly altered selectivity for various PI3K isoforms including compound 20i (8-(naphthalen-1-yl) a potent and quite selective PI3Kδ Inhibitor (IC50 = 0.64 μM). Finally, nine compounds were evaluated and showed antiproliferative activity against an NCI panel of Cancer cell lines. Compound 20i (8-(naphthalen-1-yl) showed strong anti-proliferative activity against A498 renal Cancer cells that warrants further investigation.

Keywords

Anti-cancer activity; DNA-PK; PI3K; Suzuki coupling synthesis of 8- and 6-aryl-2-morpholino-1,3-benzoxazines.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101667
    99.89%, DNA-PK Inhibitor