title: Biologically relevant O,S-donor compounds. Synthesis, molybdenum complexation and xanthine oxidase inhibition.
abstract: Two O,S-donor ligands, hydroxythiopyrone and hydroxythiopyridinone derivatives, were developed and studied, as well as the corresponding O,O-derivatives, with a view to their potential pharmacological applications as xanthine oxidase (XO) inhibitors. The biological assays revealed that the O,S-ligands present high inhibitory activity towards XO (nanomolar order, close to that of the pharmaceutical drug allopurinol), in contrast to the corresponding O,O-analogues. Due to the biomedical relevance of this molybdenum-containing enzyme, the corresponding Mo(VI) complexes were studied both in solution and in the solid state, aimed at identifying the source of the biological properties. The solution studies showed that, in comparison with the O,O-analogues, the Mo(VI) complexes with the O,S-ligands present some stabilization, which is even more pronounced for the reduced Mo(IV) species. The crystal structures of the Mo(VI) complexes with the hydroxythiopyrone revealed good flexibility of the coordination modes, with two structural isomers and two polymorphic forms for a mononuclear and a binuclear species, respectively. These results give some support to mechanistic proposals for the XO inhibition involving the interaction of the thione group with the molybdenum cofactor, thus indicating a role of the sulfur atom in the XO inhibition.
authors: Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001, Lisboa, Portugal.
authors: Sílvia
authors: S
authors: Chaves
authors: Marco
authors: M
authors: Gil
authors: Sónia
authors: S
authors: Canário
authors: Ratomir
authors: R
authors: Jelic
authors: Maria João
authors: MJ
authors: Romão
authors: José
authors: J
authors: Trincão
authors: Eberhardt
authors: E
authors: Herdtweck
authors: Joana
authors: J
authors: Sousa
authors: Carmen
authors: C
authors: Diniz
authors: Paula
authors: P
authors: Fresco
authors: M Amélia
authors: MA
authors: Santos
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D008982:Molybdenum / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry*; D013457:Sulfur Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D009942:Organometallic Compounds; D011725:Pyridines; D011753:Pyrones; D013457:Sulfur Compounds; D013871:Thiones; D000493:Allopurinol; D008982:Molybdenum; D014969:Xanthine Oxidase; D010100:Oxygen