A combined parallel synthesis and screening of macrocyclic lanthanide complexes for the cleavage of phospho di- and triesters and double-stranded DNA

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 DNB plasmid with this same complex obeyed saturation kinetics following a Michaelian model (K-m = 7.4 mu M, k(cat) = 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.