Department of Chemistry, Portland State University, 1719 SW 10th Ave., Portland, Oregon 97201, United States.
Inorg Chem. 2012 Aug 6;51(15):8576-82. doi: 10.1021/ic3011597. Epub 2012 Jul 18.
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.
镧系（III）螯合物的水交换是开发更有效的 MRI 对比剂的关键参数。我们优化水交换的努力集中在分离 LnDOTA 型螯合物的单一配位几何构型上（DOTA = 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）。通过适当取代配体框架，可以实现这种隔离，从而冻结构象交换过程，这些过程会使配位几何构型相互转换。当使用单个硝基苄基取代基来“锁定”大环环的构象时，可能会产生两种区域异构体螯合物；取代基可以替代地位于环的角或侧部。在这里，我们通过检查一些构象锁定 Eu(3+)螯合物的 COSY 谱来明确证明这种区域异构体现象。这项工作还表明，最近被认为是多异构体螯合物来源的手性中心在配体合成过程中消旋产生的非对映异构体螯合物可以被制备和分离。此外，这些 COSY 数据揭示了几个通过空间的 NOE 相关，提供了有关硝基苄基取代基构象的大量信息。在那些取代基位于环角的异构体中，硝基苄基基团大致垂直于大环平面指向上方并远离螯合物。相比之下，当取代基位于环的侧面时，硝基苄基基团大致与大环平面共面，沿螯合物的侧面指向。由于硝基的主要目的是促进化学修饰和与生物相关分子的缀合，因此这些差异可能具有重要意义。具体来说，似乎相同的螯合物可能会根据区域异构体以及因此螯合物相对于生物分子的取向，与生物系统和分子非常不同地相互作用。
