Combined chelation based on glycosyl-mono- and bis-hydroxypyridinones for aluminium mobilization: solution and biodistribution studies.
Taking into account the recognized interest of a poly-pharmacological strategy in chelation therapy, a study of aluminium combined chelation based on 3-hydroxy-4-pyridinone (3,4-HP) compounds with complementary properties, associated to different denticity, size and extrafunctionality, is presented herein. In particular, Al-chelation has been explored, using a tetradentate IDA bis-(3,4-HP) ligand, L, and two N-glycosyl mono-(3,4-HP) derivatives (A or B). Combined complexation studies with the tetradentate and the most promising bidentate ligand (A) evidenced the formation of ternary complexes with high thermodynamic stability (Al-L-A) being the predominant species at physiological pH. In vivo studies on the ability for radiotracer ((67)Ga) removal from loaded mice, as a model of aluminium accumulation in body, have shown that the simultaneous administration to (67)Ga-loaded mice of a mono- and a bis-(3,4-HP) chelator (e.g. A and L) leads to a rapid metal elimination from main organs and whole animal model. This may be rationalized by coadjuvation and eventual synergistic effects, due to complementary accessibility of the chelators to different cellular compartments.
Chaves
Sílvia
S
Centro de Química Estrutural, Instituto Superior Técnico, 1049-001 Lisboa, Portugal.
Dron
Paul I
PI
Danalache
Florina A
FA
Sacoto
Diana
D
Gano
Lurdes
L
Santos
M Amélia
MA
D000535:Aluminum / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D015913:Chelation Therapy; D005260:Female; D051379:Mice; D011728:Pyridones / Q000737:chemistry / Q000493:pharmacokinetics*; D013816:Thermodynamics; D014018:Tissue Distribution
D002614:Chelating Agents; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D000535:Aluminum