2,3-Dihydroimidazo[1,2-b]ferroceno[d]pyridazines and a 3,4-dihydro-2H-pyrimido[1,2-b]ferroceno[d]pyridazine: Synthesis, structure and in vitro antiproliferation activity on selected human cancer cell lines

•Synthesis of novel ferroceno-fused heterocycles with pronounced anticancer effects.•Analysis of the products with planar- and central chirality by 1H, 13C and 15N NMR.•Structure–activity relationships utilisable in design of anticancer drug candidates.•Products with enhanced basicity display activity comparable to that of cisplatin.

Starting from (Sp)-ferroceno[d]pyridazin-1(2H)-one a series of novel ferrocene-fused heterocycles with planar- and central chirality were synthesised. The thione analogue of the precursor obtained by treatment with Lawesson reagent underwent facile mercury-mediated aminations with a selection of aminoalcohols. The resulted intermediates were subjected to cyclisations by Appel- and Mitsunobu protocols. Two diastereomers carrying phenyl group in endo- and exo positions, respectively, in the fused metallocene scaffold underwent spontaneous oxidation affording the same planar chiral imidazo[1,2-b]ferroceno[d]pyridazine isolated as side product. The structures of the new compounds including diastereomers of different central chirality were confirmed by IR, 1H, 13C and 15N NMR spectroscopy. The in vitro antitumour activity of the fused ferrocene derivatives was investigated against HepG2 hepatoma and HT-29 colorectal adenocarcinoma cell cultures by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-assay. The measured 50% inhibitory concentration (IC50) values indicate that synthesised metallocene bases can be regarded as lead structures for the development of a novel class of heavy metal-free drug candidates with promising activity.

Graphical abstractSynthesis, structure determination and in vitro anticancer evaluation of novel imidazo- and pyrimido[1,2-b]ferroceno[d]pyridazines are reported. The models exhibit significant dose-dependent antitumour activity at micromolar concentrations on HepG2 and HT-29 tumourcell cultures.Figure optionsDownload full-size imageDownload as PowerPoint slide