title: 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.
abstract: 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 ((1)H and (13)C) spectral methods and luminescence spectroscopy. The crystal and molecular structures of [Rh(III)Cl(VIOH-1)2(PPh3)], [Rh(III)Cl(DVIOH-1)2(PPh3)] and [Rh(II)(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 [Rh(III)Cl(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.
authors.affiliation: Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain.
authors.forename: Nuria A
authors.initials: NA
authors.lastname: Illán-Cabeza
authors.affiliation: Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain.
authors.forename: Sonia B
authors.initials: SB
authors.lastname: Jiménez-Pulido
authors.affiliation: Departamento de Ciencias de la Salud, Universidad de Jaén, 23071 Jaén, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Ramírez-Expósito
authors.affiliation: Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: García-García
authors.affiliation: Departamento de Química Física y Analítica, Universidad de Jaén, 23071 Jaén, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: Peña-Ruiz
authors.affiliation: Departamento de Ciencias de la Salud, Universidad de Jaén, 23071 Jaén, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Martínez-Martos
authors.affiliation: Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain. Electronic address: mmoreno@ujaen.es.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Moreno-Carretero
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D006801:Humans; D007495:Iridium / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology; D009603:Nitroso Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012238:Rhodium / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009603:Nitroso Compounds; D011480:Protease Inhibitors; D011743:Pyrimidines; D007495:Iridium; D012238:Rhodium; D010447:Peptide Hydrolases
keywords: Antitumor activity; Crystal structure; Renin–angiotensin-system; Uracil; Violuric acid