Synthesis, cytotoxicity, QSAR, and intercalation study of new diindenopyridine derivatives

Seven new derivatives of diindenopyridine were synthesized by Hantsch pyridine synthesis. Their biological activity to inhibit cell proliferation was assessed by MTT assay on seven cell lines. 11-(4-Fluoro-phenyl)-diindeno[1,2-b;2',1'-e]pyridine-10,12-dione and 11-(2-nitro-phenyl)-diindeno[1,2-b;2',1'-e]pyridine-10,12-dione were active on K-562 cell line with IC50 values of 79.66 and 78.2 microM, respectively. Effect of structural parameters on the cytotoxicity was evaluated by quantitative structure activity relationship (QSAR) analysis and a linear relationship was found between the -logIC15 of these compounds and their surface area and molar refractivity. To model the DNA-intercalator complex, force field molecular mechanic calculation was employed and the binding energy of the reaction between the intercalating agent and each reasonable double base pairs of DNA was calculated. It was found that these molecules could intercalate into the DNA. Also, it was observed that 11-(2-nitro-phenyl)-diindeno[1,2-b;2',1'-e]pyridine-10,12-dione, which showed the highest activity in K-562 cell line, produced the most negative binding energy with a moderate selectivity toward A-G/T-C double base pairs.