Effective repression of the fragmentation of a hexadentate ligand bearing an auto-immolable pendant arm by iron coordination

A diamagnetic ferrous complex (1) (MRI silent) is presented that consists of a macrocyclic hexadentate ligand (7) bearing an auto-immolable arm, as seen in organic prodrug design. This arm constitutes a phenylogous N/O acetal locked by glycosylation. Enzymatic glycolysis is hypothesized to lead to a phenol intermediate (a phenylogous hemiaminal) that fragments spontaneously thereby liberating a paramagnetic ferrous complex (MRI active). This paper describes the synthesis of ligand 7 and complex 1, and their respective reaction with P-galactosidase, the target enzyme. While ligand 7 alone fragments swiftly to the pentadentate ligand dptacn (monitored by LCMS analysis) upon in vitro enzymatic conversion, the phenol resulting from glycosyl removal from complex I accumulates in the buffered reaction mixture without any apparent fragmentation. Two independent explanations are put forward: metal coordination leads to rigidification of the ligand skeleton with concomitant kinetic inhibition of fragmentation or to the liberation of enough extra free energy to shift the thermodynamic equilibrium towards the starting material. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).