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

TETRAHEDRON

卷:73

Article

Jernei, Tamas¹  Bosze, Szilvia²  Szabo, Rita²  Hudecz, Ferenc^2,3  Majrik, Katalin⁴  Csampai, Antal¹ 

[1] Eotvos Lorand Univ, Dept Inorgan Chem, Pazmany P Setany 1-A, H-1117 Budapest, Hungary

[2] MTA ELTE Res Grp Peptide Chem, Pazmany P Setany 1-A, H-1117 Budapest, Hungary

[3] Eotvos Lorand Univ, Dept Organ Chem, Pazmany P Setany 1-A, H-1117 Budapest, Hungary

[4] Hungarian Acad Sci, Res Ctr Nat Sci, Magyar Tudosok Korutja 2, H-1117 Budapest, Hungary

关键词: Pyridazine;    Lactams;    N-arylation;    Ferrocene;    Cytotoxicity;    SAR;    Cyclic voltammetry;    HOMO energy;    Ionization energy;   

DOI  :  10.1016/j.tet.2017.09.015

来源: Elsevier

【 摘 要 】

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. (C) 2017 Elsevier Ltd. All rights reserved.

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