Structural and theoretical studies on rhodium and iridium complexes with 5-nitrosopyrimidines. Effects on the proteolytic regulatory enzymes of the renin–angiotensin system in human tumoral brain cells

• Sixteen rhodium and iridium complexes with 5-nitrosopyrimidines are reported.
• The crystal structures of three complexes have been determined.
• Metal–ligand bonds and some intermolecular interactions are studied (AIM theory).
• Compounds show low direct toxicity against the human NB69 and U373-MG cells.
• The activity could be exerted through the paracrine regulating system mediated by RAS.

The reactions of [RhCl(CO)(PPh3)2], [RhCl(CO)2]2 and [IrCl(CO)(PPh3)2] with different 5-nitrosopyrimidines afforded sixteen complexes which have been structurally characterized by elemental analysis, IR and NMR (1H and 13C) spectral methods and luminescence spectroscopy. The crystal and molecular structures of [RhIIICl(VIOH− 1)2(PPh3)], [RhIIICl(DVIOH− 1)2(PPh3)] and [RhII(DVIOH− 1)2(PPh3)2] have been established from single crystal x-ray structure analyses. The three complexes are six-coordinated with both violurato ligands into an equatorial N5,O4-bidentate fashion, but with different mutually arrangements. Theoretical studies were driven on the molecular structure of [RhIIICl(VIOH− 1)2(PPh3)] to assess the nature of the metal–ligand interaction as well as the foundations of the cis–trans (3L–2L) isomerism. An assortment of density functional (SOGGA11-X, B1LYP, B3LYP, B3LYP-D3 and wB97XD) has been used, all of them leading to a similar description of the target system. Thus, a topological analysis of the electronic density within AIM scheme and the study of the Mulliken charges yield a metal–ligand link of ionic character. Likewise, it has been proved that the cis–trans isomerism is mainly founded on that metal–ligand interaction with the relativistic effects playing a significant role. Although most of the compounds showed low direct toxicity against the human cell lines NB69 (neuroblastoma) and U373-MG (astroglioma), they differently modify in several ways the renin–angiotensin system (RAS)-regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP). Therefore, these complexes could exert antitumor activity against both brain tumor types, acting through the paracrine regulating system mediated by tissue RAS rather than exerting a direct cytotoxic effect on tumor cells.

Sixteen Rh and Ir complexes with 5-nitrosopyrimidines have been characterized from both experimental (including XRD) and theoretical methods. The antitumor activity against neuroblastoma NB69 and astroglioma U373-MG human brain tumor cells could be exerted acting through the paracrine regulating system mediated by tissue RAS rather than exerting a direct cytotoxic effect.Figure optionsDownload as PowerPoint slide