N-ferrocenylpyridazinones and new organic analogues: Synthesis, cyclic voltammetry, DFT analysis and in vitro antiproliferative activity associated with ROS-generation

5 years ago

N-ferrocenylpyridazinones and new organic analogues: Synthesis, cyclic voltammetry, DFT analysis and in vitro antiproliferative activity associated with ROS-generation

Employing an optimized Pd-catalyzed cross-coupling reaction promoted by CuI, novel N-ferrocenylpyridazinones along with N-phenyl- and N-(2-pyridyl) analogues were synthesized from readily available heterocyclic precursors, iodoferrocene, iodobenzene and 2-bromopyridine. With exception of the ferrocenylation of 6-ferrocenylpyridazin-3(2H)-one yielding both N- and O-substituted products, the studied reactions exclusively afforded N-aryl lactams. The novel compounds exhibited cytotoxicity towards HEPG2 and HT-29 human malignant cells under in vitro conditions. The measured IC50 values supplemented with the results of cyclic voltammetry and DFT calculations suggest that the cytotoxic activity of the N- and O-ferrocenyl-substituted derivatives and the decreased effect of the N-phenyl analogues seem to be at least partly associated with the potential to generate reactive oxygen species (ROS). This interpretation, allowing the prediction of characteristic substituent-dependent SAR, was supported by the results of related studies on the practically inactive N-(2-pyridyl)pyridazinones assumed to be present in protonated chelate forms with highly a decreased propensity to undergo ionization.

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DOI: S0040402017309377