ABSTRACT
A facile one-pot method for the synthesis of new phenanthrene fused-dihydrodibenzo-quinolinone derivatives has been successfully accomplished by employing sulfamic acid as catalyst. These new compounds were evaluated for their in vitro cytotoxic potential against human lung (A549), prostate (PC-3 and DU145), breast (MCF-7) and colon (HT-29 and HCT-116) cancer cell lines. Among all the tested compounds, one of the derivatives 8p showed good anti-proliferative activity against A549 lung cancer cell line with an IC50 of 3.17⯱â¯0.52⯵M. Flow cytometric analyses revealed that compound 8p arrested both Sub G1 and G2/M phases of cell cycle in a dose dependent manner. The compound 8p also displayed significant inhibition of tubulin polymerization and disruption of microtubule network (IC50 of 5.15⯱â¯0.15⯵M). Molecular docking studies revealed that compound 8p efficiently interacted with critical amino acid Cys241 of the α/ß-tubulin by a hydrogen bond (SH Oâ¯=â¯2.4â¯Å). Further, the effect of 8p on cell viability was also studied by AO/EB, DCFDA and DAPI staining. The apoptotic characteristic features revealed that 8p inhibited cell proliferation effectively through apoptosis by inducing the ROS generation. Analysis of mitochondrial membrane potential through JC-1 staining and annexin V binding assay indicated the extent of apoptosis in A549 cancer cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Quinolones/chemistry , Sulfonic Acids/chemistry , Tubulin Modulators/chemical synthesis , Tubulin/metabolism , A549 Cells , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Binding Sites , Cell Cycle Checkpoints/drug effects , Drug Screening Assays, Antitumor , Humans , Membrane Potential, Mitochondrial/drug effects , Molecular Docking Simulation , Phenanthrenes/chemistry , Protein Structure, Tertiary , Quinolones/metabolism , Quinolones/pharmacology , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Tubulin/chemistry , Tubulin Modulators/metabolism , Tubulin Modulators/pharmacologyABSTRACT
A series of new phenanthrene-9-benzimidazole conjugates has been synthesized by condensing phenanthrene aldehydes with various substituted o-phenylenediamines. The title compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines like breast (BT-549), prostate (PC-3 and DU145), triple negative breast cancer (MDA-MB-453), and human colon cancer (HCT-116 and HCT-15) cells. Among the tested compounds, 10o displayed significant in vitro cytotoxic activity against PC-3 prostate cancer cells with an IC50 value of 6.32 ± 0.09 µM. Further, the cell cycle analysis indicated that it blocks G2/M phase of the cell cycle in a dose dependent manner. In order to determine the effect of the compound 10o on cell viability; phase contrast microscopy, AO/EB staining, DAPI staining, and DCFDA staining studies were performed. In these studies, apoptotic features were clearly observed indicating that the compound inhibited cell proliferation by apoptosis. JC-1 staining and annexin binding assays indicated the extent of apoptosis in PC-3 cells. Further, relative viscosity measurements and molecular docking studies indicated that these compounds bind to DNA by intercalation.
