Structural analysis of isomeric europium(III) chelates of NB-DOTMA.
Water exchange in lanthanide(III) chelates is a key parameter in developing more effective MRI contrast agents. Our own efforts to optimize water exchange have focused on isolating single coordination geometries of LnDOTA-type chelates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate.) This isolation may be achieved by appropriately substituting the ligand framework to freeze-out the conformational exchange processes that interconvert coordination geometries. When a single nitrobenzyl substituent is used to "lock" the conformation of the macrocyclic ring, two regioisomeric chelates may be produced; the substituent may be alternatively located on the corner or the side of the ring. Here, we unambiguously demonstrate this regioisomerism by examining the COSY spectra of some conformationally locked Eu(3+) chelates. This exercise also demonstrated that diastereoisomeric chelates arising from racemization of chiral centers during the ligand synthesis, recently discounted as the origin of multiple isomeric chelates, can be produced and isolated. Furthermore, these COSY data revealed several through space NOE correlations that afford a great deal of information about the conformation of the nitrobenzyl substituent. In those isomers in which the substituent is located on the corner of the ring, the nitrobenzyl group is oriented approximately perpendicular to the plane of the macrocycle pointing upward and away from the chelate. In contrast, when the substituent is located on the side of the ring, the nitrobenzyl group is oriented approximately in plane with the macrocycle, pointing along the side of the chelate. Because the main purpose of the nitro group is to facilitate chemical modification and conjugation to biologically relevant molecules, these differences may have important consequences. Specifically, it seems likely that the same chelate may interact very differently with biological systems and molecules depending upon the regioisomer and therefore the orientation of the chelate relative to the biomolecule.
Department of Chemistry, Portland State University, 1719 SW 10th Ave., Portland, Oregon 97201, United States.
Benjamin C
BC
Webber
Mark
M
Woods
D002614:Chelating Agents / Q000737:chemistry*; D003287:Contrast Media / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry*; D005063:Europium / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry*
D002614:Chelating Agents; D003287:Contrast Media; D056831:Coordination Complexes; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; D014867:Water; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D005063:Europium; D005682:Gadolinium