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

• Published in: Medicinal chemistry research 2016-08, Vol.25 (8), p.1695-1704
• Main Authors: Heppell, Jacob T., Al-Rawi, Jasim M. A.
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Original Research; Pharmacology/Toxicology
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-016-1608-9

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 =CH 2 (pyridine-4-yl)) displayed selective phosphoinositide 3-kinase delta activity with 80 % inhibition at 10 µM. Similarly, compounds 5a (8- N -substituted, R =CH 2 Ph) and 3a (7- N -substituted, R =CH 2 Ph) 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-CH 2 (pyridine-3-yl) substituents was found to be the most active (IC 50 35 µM).