RESUMEN
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.
Asunto(s)
Quelantes/síntesis química , Quelantes/farmacología , Difosfonatos/síntesis química , Difosfonatos/farmacología , Uranio/química , Uranio/farmacocinética , Animales , Sitios de Unión , Huesos/efectos de los fármacos , Huesos/metabolismo , Quelantes/química , Difosfonatos/química , Riñón/efectos de los fármacos , Riñón/metabolismo , Ligandos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Estereoisomerismo , Distribución Tisular/efectos de los fármacos , Uranio/orinaRESUMEN
New tripodal gem-(bis-phosphonates) uranophiles were discovered by a screening method that allowed for the selection of ligands with strong uranyl-binding properties in a convenient microtiter-plate format. The method is based on competitive uranium binding by using Sulfochlorophenol S as chromogenic chelate. This dye compound was found to present high uranyl complexation properties and allowed to highlight ligands presenting association constants for UO(2+)(2) up to 10(18) at pH 7.4 and 10(20) at pH 9. A collection of 40 known ligands including polycarboxylate, hydroxamate, catecholate, hydroxypyridonate and hydroxyquinoline derivatives was tested. Also screened was a combinatorial library prepared from seven amine scaffolds and eight acrylates bearing diverse chelating moieties. Among these 96 tested candidates, a tripod derivative bearing gem-bis-phosphonates moieties was found to present the highest complexation properties over a wide range of pH and was further studied.