Antiproliferative effects of palladium(II) complexes of 5-nitrosopyrimidines and interactions with the proteolytic regulatory enzymes of the renin–angiotensin system in tumoral brain cells

• Seventeen Pd(II) complexes with 5-nitrosopyrimidine ligands have been reported.
• Neutral pyrimidines bind to metal through N5 (nitroso) and O4 (carbonyl).
• Deprotonated pyrimidines coordinates through N5 (nitroso) and N6 (imino).
• A good antiproliferative activity against human NB69 and U373 cells has been found.
• Complexes modify the proteolytic regulatory enzymes of RAS in a different way.

Seventeen new palladium(II) complexes of general formulaes PdCl2L, PdCl(LH− 1)(solvent) and PdCl2(PPh3)2L containing pyrimidine ligands derived from 6-amino-5-nitrosouracil and violuric acid have been prepared and characterized by elemental analysis, IR and NMR (1H and 13C) methods and, two of them, PdCl(DANUH− 1)(CH3CN)]·½H2O and [PdCl(2MeOANUH− 1)(CH3CN)] by X-ray single-crystal diffraction (DANU: 6-amino-1,3-dimethyl-5-nitrosouracil; 2MeOANU: 6-amino-2-methoxy-5-nitroso-3H-pyrimidin-4-one). The coordination environment around palladium is nearly square planar in the two compounds with different supramolecular arrangements. Crystallographic and spectral data are consistent with a bidentate coordination mode through N5 and O4 atoms when the ligands act in neutral form and N5 and N6 atoms in the monodeprotonated ones. The cytotoxicity of the complexes against human neuroblastoma (NB69) and human glioma (U373-MG) cell lines has been tested showing a considerable antiproliferative activity. Also, the study of the effects of palladium(II) complexes on the renin–angiotensin system (RAS) regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP) shows a strong dependence on the compound tested and the tumoral cell type, also affecting different catalytic routes; the compounds affect in a different way the activities of enzymes of the RAS system, changing their functional roles as initiators of cell proliferation in tumors as autocrine/paracrine mediators.

Seventeen new palladium(II) complexes of general formulaes PdCl2L, PdCl(LH− 1)(solvent) and PdCl2(PPh3)2L containing ligands derived from 6-amino-5-nitrosouracil and violuric acid are reported. Data indicate N,O (neutral) and N,N (anionic) bidentate coordination modes. The antiproliferative activity against human neuroblastoma (NB69) and human glioma (U373) cell lines and the interaction with the proteolytic regulatory enzymes of renin–angiotensin system are also reported.Figure optionsDownload as PowerPoint slide