Design, synthesis and biological evaluation of novel benzo- and tetrahydrobenzo-[h]quinoline derivatives as potential DNA-intercalating antitumor agents

A new series of benzo- and tetrahydro benzo-[h]quinoline bearing a flexible (dimethylamino)ethylcarboxamide side chain was designed and synthesized as DNA-intercalating antitumor agents. The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including MCF-7, A2780, C26 and A549. In general, saturated quinolines (tetrahydrobenzo[h]quinolines) exhibited more cytotoxicity compared to their corresponding unsaturated quinolines (benzo[h]quinolines). Compound 6e showed significant cytotoxicity against all four human cancer cell lines with IC50 values ranging from 1.86 to 3.91 μM. The interaction of the selected compounds showed significant cytotoxicity (6b, 6e, 6i and 6j) with calf thymus DNA (CT-DNA) was studied by UV and florescent spectroscopy. In general, benzo[h]quinolines showed higher interacting effect with DNA than their corresponding saturated tetrahydrobenzo[h]quinolines. Compound 6i exhibited the most DNA intercalating effects among the series. The apoptotic induction potential of the most cytotoxic compounds (6e, 6b and 6i) in A549 cells was studied using Annexin V-FITC/Propidium iodide staining assay. Compound 6e which showed the most cytotoxic effect against A549 cancer cells also exhibited stronger apoptotic induction activity in comparison with 6b and 6i.The docking was performed in order to study the DNA interaction properties of these compounds. According to the computational data, these compounds can interact with DNA as DNA-intercalating agents. We report here, the molecular design and chemical synthesis of a series of novel benzo- and tetrahydro benzo-[h]quinoline bearing a flexible (dimethylamino)ethylcarboxamide side chain at position-4 of quinoline similar to some known DNA-intercalating agents. The rationale for the design of these quinolines is depicted in the following figure. Compound 6i, from benzo[h]quinoline group possessing three fused aromatic rings and methyl group at para position of phenyl ring, showed the best intercalative properties among newly synthesized quinolines, and also showed the lowest binding energy (kcal/mol) in molecular modeling study, more than its corresponding unsaturated compound 6b possessing two fused aromatic rings. [Display omitted] •Novel benzo- and tetrahydro benzo-[h]quinolines were designed and synthesized as DNA-intercalating antitumor agents.•Compound 6e showed significant cytotoxic activity against cancer cells lines with IC50 values ranging from 1