Synthesis, structures elucidation, DNA-PK, PI3K and antiplatelet activity of a series of novel 7- or 8-(N-substituted)-2-morpholino-quinazolines
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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).
KeywordsDNA-PK PI3K Antiplatelet 2-morpholino quinazolines
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interests.
Ethics approval for the use of human blood was obtained from La Trobe University Human Ethics Committee (HEC13-010).
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