Complexes of hydroxy(thio)pyrone and hydroxy(thio)pyridinone with Zn(II) and Mo(VI). Thermodynamic stability and insulin-mimetic activity.
The development of metal-containing pharmaceuticals as insulin-mimetics has been the object of recent worldwide research. We have examined a series of zinc(II) and molybdenum(VI) complexes with model O,S-donor ligands (thiomaltol and 1,2-dimethyl-3-hydroxypyridine-4-thione (DMHTP)) and the corresponding O,O-analogues (maltol and DMHP) for their insulin-mimetic activity. Aimed at getting structure-activity relationships, some physical-chemical properties were also studied, such as metal-complex formation, speciation at different pH conditions and ligand lipophilicity. The Zn-complexes exhibit considerably higher insulin-mimetic activity than the corresponding Mo-analogues. Particularly, the bis(thiomaltolato)zinc(II) complex reveals a very high activity, ascribed to the effect of the thione π character and to the soft nature of the sulfur donor atom enhancing the Zn(II)-ligand affinity and the ligand/complex lipophilicity, two determinant parameters for delivering the metal-drug into the cells. Hence, these preliminary studies indicate that the Zn(thiomaltol)₂ complex can be considered a potential drug candidate for treatment of diabetes mellitus, upon in vivo evaluations.
Centro de Química Estrutural, Instituto Superior Técnico, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
Sílvia
S
Chaves
Ratomir
R
Jelic
Catarina
C
Mendonça
Marta
M
Carrasco
Yutaka
Y
Yoshikawa
Hiromu
H
Sakurai
M Amélia
MA
Santos
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D055598:Chemical Phenomena; D004355:Drug Stability; D004837:Epinephrine / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000378:metabolism; D007328:Insulin / Q000031:analogs & derivatives; D008982:Molybdenum / Q000737:chemistry* / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism; D011753:Pyrones / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013457:Sulfur Compounds / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D017967:Zinc Compounds / Q000737:chemistry* / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D011728:Pyridones; D011753:Pyrones; D013457:Sulfur Compounds; D017967:Zinc Compounds; D008982:Molybdenum; D004837:Epinephrine