Biologically relevant O,S-donor compounds. Synthesis, molybdenum complexation and xanthine oxidase inhibition.
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.
Chaves
Sílvia
S
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001, Lisboa, Portugal.
Gil
Marco
M
Canário
Sónia
S
Jelic
Ratomir
R
Romão
Maria João
MJ
Trincão
José
J
Herdtweck
Eberhardt
E
Sousa
Joana
J
Diniz
Carmen
C
Fresco
Paula
P
Santos
M Amélia
MA
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
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