Ligand Design for N,O- or N,N-Pyrazolone-Based Hydrazones Ruthenium(II)-Arene Complexes and Investigation of Their Anticancer Activity

Three pyrazolone-based hydrazone ligands HL' (HL' in general; in detail, HL1 = 24(5-hydroxo-3-methy1-1ph enyl- 1H-pyr az ol- 4-y1) (ph enyl)me thyl en e)-1- (2,4nitrophenyOhydrazine, HL2 = 24(5-hydroxo-3-methy1-1-pheny1-1H-pyrazol-4-71) (phenyl) methylene)-1- ( 4-nitrophenyl) hydrazine, and HL3 = 24(5-hydroxo-3-methyl-l-pheny1-1Hpyrazol-4-y1)(phenyOmethylene)-1-(pyridin-2-yphydrazine) have been prepared starting from 4-benzoy1-3-methy1-1-phenyl-1H-pyrazol-5(4H)-one and fully characterized in the solid state and solution, where the existing tautomeric forms were identified by taking advantage of natural abundance H-1-15N coupling in {H-1-N-15}-HSQC and 1/4-15-1_ HMBC NMR spectroscopy. Then, six half-sandwich arene-ruthenium(II) derivatives (arene = hexamethylbenzene and p-cymene) of composition [(arene)Ru(L')Cl] have been synthesized and fully characterized by IR, H-1, and C-13 NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and density functional theory calculations. The crystal structures of three complexes, together with the E configurational isomer (with respect to the C=N double bond) of the free proligand HL2 and the zwitterionic proligand HL3 were determined by X-ray analysis. The anionic ligands L1 and L2 were found bonded to ruthenium in the N,O-form, while L3 coordinates the metal in the N,N-form affording five-membered chelating rings. The cytotoxicity of the complexes was evaluated against human breast adenocarcinoma cells (MCF-7 and MCF-7CR), as well as against nontumorigenic human breast (MCF-10A) cells and compared to the free ligand and cisplatin.