Synthesis, structures elucidation, DNA-PK, PI3K and antiplatelet activity of a series of novel 7- or 8-(N-substituted)-2-morpholino-quinazolines

Abstract

The DNA-dependent protein kinase and phosphoinositide 3-kinase family is one of the most frequently activated enzymes in a wide range of human cancers; consequently, inhibition of DNA-dependent protein kinase and phosphoinositide 3-kinase represents an approach for cancer therapy. In this work, we have designed and synthesized a series of novel 7- or 8-(N-substituted)-2-morpholino quinazolines 3a–f, 5a–e, 7a–e, and 9 from 7- or 8-amino-2-morpholino quinazolin-4-ones (2a, 4a), the 3-methyl analogues (2b, 4b) and the 4-alkyloxy analogues (6a–b, 8). The compounds were subsequently assayed for DNA-dependent protein kinase and phosphoinositide 3-kinase activity. Most compounds were less active than expected in spite of the strong structural resemblance to the previously studied 7- or 8-(O-substituted)-2-morpholino-1,3-benzoxazine inhibitors. Loss of DNA-dependent protein kinase activity for the quinazolin-4-ones (3a–d and 5a–d) has been attributed to tautomerization to the aromatic enol (4-OH) tautomers. Aromatization of the heterocyclic ring could alter the conformation, and thus binding position, resulting in reduced compound-receptor hydrogen bonding of the morpholine oxygen and 4-carbonyl oxygen. The hetero-aromatic compounds 7a–e and 9 also did not show any DNA-dependent protein kinase activity at 10 µM, which supports the above hypothesis. Compound 7c (R=CH₂(pyridine-4-yl)) displayed selective phosphoinositide 3-kinase delta activity with 80 % inhibition at 10 µM. Similarly, compounds 5a (8-N-substituted, R=CH₂Ph) and 3a (7-N-substituted, R=CH₂Ph) showed selective phosphoinositide 3-kinase beta activity with 69 and 61 % inhibition, respectively. Antiplatelet inhibition assays showed that compound 7e with the 4-O-benzyloxy group and 8-CH₂(pyridine-3-yl) substituents was found to be the most active (IC₅₀ 35 µM).