New strategies for the synthesis of naphthoquinones employing Cu(II) complexes: Crystal structures and cytotoxicity

Abstract

The syntheses, physico-chemical characterization and cytotoxicity toward three human cell lines (standard and resistant sarcoma cells, and fibroblast) of a new copper(II) complex [Cu(HBPA)(L1)Cl]·3H2O 2 are reported. Complex 2 was obtained through the reaction between the ligand stilbene-quinone (HL1) and Cu[HBPA]Cl21, where HBPA = 2-hydroxybenzyl-2pyridylmethylamine. The synthesis of HL1 was performed in high yield through Heck reaction on PEG-400. X-ray diffraction and solution studies (UV–Vis, EPR, ESI(+)−MS and ESI(+)−MS/MS) were performed for complex 2, in which the copper(II) center is coordinated to the quinone in its deprotonated form, to the ligand HBPA and to a chloro ligand. Similar reaction employing CuCl2·2H2O, instead of Cu[HBPA]Cl21 and HL1, has resulted in the obtainment of a furano-o-naphtoquinone (L2) with 99% selectivity, suggesting a new methodology to cyclize the ligand HL1. In order to obtain the analogous para-isomer (L3), and to evaluate the isomerism influence on cytotoxicity activity, a cyclization reaction of HL1 with NBS (N-bromosuccinimide) was also performed, which resulted in the obtainment of L2 (8%) and L3 (13%). X-ray diffraction studies were performed for L2 and complex 2, and the description of their structure elucidated. Results from MTT assay revealed that complex 2 is more active against sarcoma cell lines (MES-SA/Dx5 and MES-SA) than both the free ligand HL1 and complex 1, reducing cell viability to less than 50 μmol L−1. L2 was the most active in the series, presenting cytotoxicity against resistant MES-SA/Dx5 and its standard MES-SA cell line, respectively, three and ten times higher than the current drug doxorubicin.