Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 110, Issue -, Pages 326-339Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.01.042
Keywords
Suzuki coupling synthesis of 8-and 6-aryl-2-morpholino-1,3-benzoxazines; DNA-PK; PI3K; Anti-cancer activity
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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 mu M) was identified as a specific DNA-PM inhibitor, 170 fold more selective for DNA-PM 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 PI3M delta inhibitor (IC50 = 0.64 mu M). 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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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