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

The 2-morpholino-substituted-benzoxazines 7a and 7b were used in the synthesis of 2-morpholino-di-Obenzyl, 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) alpha, beta, gamma, and delta isoforms were studied for the new compounds 8a-8f and PI3K for the 18 previously synthesized compounds 9-26. The most active DNA-PK inhibitors were the 2-morpholino-O-substituted linear or angular naphthoxazine compounds 18-20 and 21-22 which showed potent and selective DNA-PK activity (IC50 from 0.01 to 2.43 mu M) 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 10-12 (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.