Mechanistic Investigation of β-Galactosidase-Activated MR Contrast Agents

We report a mechanistic investigation of an isomeric series of β-galactosidase-activated magnetic resonance contrast agents. Our strategy focuses on the synthesis of macrocyclic caged-complexes that coordinatively saturate a chelated lanthanide. Enzyme cleavage of the complex results in an open coordination site available for water that creates a detectable MR contrast agent. The complexes consist of a DO3A Gd(III) chelator modified with a galactopyranose at the N-10 position of the macrocycle. We observed significant differences in relaxometric properties and coordination geometry that can be correlated to subtle variations of the linker between the macrocycle and the galactopyranose. After synthesis and purification of the R, S, and racemic mixtures of complexes 1 and 3 and measurement of the hydration number, water residence lifetime, and longitudinal relaxation rates, we propose mechanisms for water exclusion from the lanthanide in the precleavage state. While the stereochemistry of the linker does not influence the agents' properties, the mechanism of water exclusion for each isomer is significantly influenced by the position of modification. Data for one series with a methyl group substituted on the sugar-macrocycle linker at the α-position suggests a steric mechanism where the galactopyranose sugar blocks water from the Gd(III) center. In contrast, our observations for a second series with methyl substitution at the β position of the sugar-macrocycle linker are consistent with a mechanism in which a bidentate anion occupies two available coordination sites of Gd(III) in the precleavage state

Transition metal complexes supported by tris(phosphino) borate ligands

Our group is currently targeting charge neutral metal complexes that exhibit chemistry reminiscent of cationic, coordinatively unsaturated species. Within this context we have set out to prepare new metal complexes bearing anionic tris-phosphino borate ligands, [PhB(CH2PPh2)3]-, and have thus far succeeded in isolating and characterizing a range of molecular complexes ranging from the mid to latter part of the transition series. For example, the cobalt(II) complexes {PhB(CH2PPh2)3]CoX}2 (X=CI, Br) have been prepared and shown to be dimeric in the solid state. The related iodide complex PhB(CH2PPh2)3]Col, however, is rigorously monomeric in the solid state and represents an unusual 15 electron cobalt complex. The physical and chemical properties of these and other compounds will be discussed, in addition to our recent efforts at expanding the toolkit of tris-phosphino borate ligands