Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation, DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones

摘要

A series of novel 8-aryl-2-morpholino quinazolines (11a-n, 12a-d, 14a-f, and 15) were synthesized from the precursor 2-thioxo quinazolin-4-ones 8. The 8-aryl-2-morpholino quinazolines compounds were assayed for DNA-PK and PI3K. All compounds showed low DNA-PK % inhibition activity at 10 mu M compound concertation, and the most active was 8-(dibenzo[b,d]thiophen-4-yl) 12d with 38% inhibition. Similar pattern of PI3K alpha, beta, gamma, and delta isoforms inhibition activity at 10 mu M were observed. The most active isoform was PI3K delta of 41% inhibition for 8-(dibenzo[b,d]furan-4-yl) compound 11. Most compounds were less active than expected in spite of the strong structural resemblance to known inhibitors (NU7441, 3, 4, and 6). Loss of activity could be attributed to the tautomerization to the aromatic enol (4-OH), which could specify that the important functional group for the activity is the 4-carbonyl (C=O) group. Alternatively, the aromatization of the pyrimidine heterocyclic ring could alter the conformation, and thus binding site, of the 2-morpholine ring, which could reduce the compound-receptor hydrogen bonding to the morpholine 4-oxygen. Selected compounds displayed appreciable cytotoxicity with 6-chloro-8-(dibenzo[b,d]thiophen-4-yl)-2-morpholinoquinazolin-4(1H)-one 11j exhibiting the greatest activity with an IC50 of 9.95 mu M. Therefore, the mechanism of the cytotoxicity of compound 11j were not through DNA-PK or PI3K inhibition activity.