4-Aminoquinoline derivatives as potent inhibitors of pancreatic cancer: Synthesis, evaluation and docking studies.

Abstract

Herein we describe synthesis and evaluation of 4-aminoquinoline derivatives as anticancer agents. By using Friedlander type condensation and cyclization reactions, the new compounds were synthesized in one-pot from commercially available anthranilonitriles and substituted acetophenones in excellent yields. All the new compounds were purified, fully characterized, and evaluated for in vitro anticancer activity against different cancer cell lines HeLa (human cervical carcinoma), MIA PaCa-2 (pancreatic cancer), PANC-1(pancreatic cancer), SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Compound 3g was found to be the most potent derivative among all the tested compounds against five cancer cell lines, with 50 % inhibition concentration, IC50 of 3.85±0.16, 3.75±0.32, 3.8 ± 0.13, 4.29±0.56, and 5.13±0.78 μM, respectively, with the lowest IC50 value in MIA PaCa-2 cancer cells. The exact mechanism of action of 3g was therefore investigated in MIA-PaCa-2 cells. The results show that 3g induces dose-dependent cell cycle arrest during the G2/M phase. Furthermore, downregulation of the expression of cell cycle marker proteins, such as that of cyclin B1 and Cdc25C, was found to be the reason for the termination of the G2/M phase. Furthermore, docking analysis of the promising compounds 3f, 3g, 3i, and 3j revealed the most efficient molecular interactions with the target protein cyclooxygenase-2 (PDB ID: 1CX2). Overall, 3 g could prove to be an effective agent for treating pancreatic cancer.