Bisphosphonate sequestering agents. Synthesis and preliminary evaluation for in vitro and in vivo uranium(VI) chelation.
A library of bisphosphonate-based ligands was prepared using solution-phase parallel synthesis and tested for its uranium-binding properties. With the help of a screening method, based on a chromophoric complex displacement procedure, 23 dipodal and tripodal chelates bearing bisphosphonate chelating functions were found to display very high affinity for the uranyl ion and were selected for evaluation of their in vivo uranyl-removal efficacy. Among them, 11 ligands induced a huge modification of the uranyl biodistribution by deviating the metal from kidney and bones to liver. Among the other ligands, the most potent was the dipodal bisphosphonate 3C which reduced the retention of uranyl and increased its excretion by around 10% of the injected metal.
Sawicki
Marcin
M
Service de Chimie Bio-organique et de Marquage, iBiTec-S, CEA-Saclay, 91191 Gif sur Yvette, France.
Lecerclé
Delphine
D
Grillon
Gérard
G
Le Gall
Béatrice
B
Sérandour
Anne-Laure
AL
Poncy
Jean-Luc
JL
Bailly
Théodorine
T
Burgada
Ramon
R
Lecouvey
Marc
M
Challeix
Vincent
V
Leydier
Antoine
A
Pellet-Rostaing
Stephane
S
Ansoborlo
Eric
E
Taran
Frédéric
F
D000818:Animals; D001665:Binding Sites; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014018:Tissue Distribution / Q000187:drug effects; D014501:Uranium / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine
D002614:Chelating Agents; D004164:Diphosphonates; D008024:Ligands; D054852:Small Molecule Libraries; D014501:Uranium