title: A combined parallel synthesis and screening of macrocyclic lanthanide complexes for the cleavage of phospho di- and triesters and double-stranded DNA.
abstract: A parallel synthesis of macrocyclic lanthanide-ligand complexes 4Ln has been developed in conjunction with a parallel screening of these ligands for catalysis of phosphate ester hydrolysis. Complexes 4Ln were screened on a 96-well plate reader for their ability to catalyze the hydrolysis of a variety of phosphate esters efficiently. The hydrolysis of bis(4-nitrophenyl) phosphate (BNPP) 5 and p-nitrophenylethyl phosphate 6 was accelerated by up to 150-fold in the presence of the complex 4cGd. The cleavage of a double-stranded DNA plasmid with this same complex obeyed saturation kinetics following a Michaelian model (K(m) = 7.4 microM, kcat = 4.5 x 10(-3) min-1). Our findings demonstrate how a combination of parallel synthesis and screening can expedite compound access, accelerate catalyst identification, and thereby dramatically increase the speed of finding good ligand-metal combinations.
authors.affiliation: Scripps Research Institute, Department of Chemistry, La Jolla, California, USA.
authors.forename: T
authors.initials: T
authors.lastname: Berg
authors.forename: A
authors.initials: A
authors.lastname: Simeonov
authors.forename: K D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D004952:Esters / Q000737:chemistry; D006868:Hydrolysis; D007700:Kinetics; D008674:Metals, Rare Earth / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010710:Phosphates / Q000737:chemistry; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D004952:Esters; D008674:Metals, Rare Earth; D010710:Phosphates; D004247:DNA