Abstract
The antitumor activity of newly synthesised triazolophthalazines (L-45 analogues) 10-32 was evaluated in human hepatocellular carcinoma (HePG-2), breast cancer (MCF-7), prostate cancer (PC3), and colorectal carcinoma (HCT-116) cells. Compounds 17, 18, 25, and 32 showed potent antitumor activity (IC
, 2.83-13.97 μM), similar to doxorubicin (IC
, 4.17-8.87 μM) and afatinib (IC
, 5.4-11.4 μM). HePG2 was inhibited by compounds 10, 17, 18, 25, 26, and 32 (IC
, 3.06-10.5 μM), similar to doxorubicin (IC
, 4.50 μM) and afatinib (IC
, 5.4 μM). HCT-116 and MCF-7 were susceptible to compounds 10, 17, 18, 25, and 32 (IC
, 2.83-10.36 and 5.69-11.36 μM, respectively), similar to doxorubicin and afatinib (IC
= 5.23 and 4.17, and 11.4 and 7.1 μM, respectively). Compounds 17, 25, and 32 exerted potent activities against PC3 (IC
, 7.56-12.28 μM) compared with doxorubicin (IC
, 8.87 µM) and afatinib (IC
7.7 μM). Compounds 17 and 32 were the strongest PCAF inhibitors (IC
, 5.31 and 10.30 μM, respectively) and compounds 18 and 25 exhibited modest IC
values (17.09 and 32.96 μM, respectively) compared with bromosporine (IC
, 5.00 μM). Compound 17 was cytotoxic to HePG2 cells (IC
, 3.06 μM), inducing apoptosis in the pre-G phase and arresting the cell cycle in the G2/M phase. Molecular docking for the most active PCAF inhibitors (17 and 32) was performed.