Raymond Jaclyn J, Chowdhury Md Saiful I, Crawley Matthew R, Morrow Janet R
Department of Chemistry, University at Buffalo, the State University of New York, Amherst, NY 14260.
Chemistry. 2024 Aug 22;30(47):e202401638. doi: 10.1002/chem.202401638. Epub 2024 Jul 31.
Macrocyclic Co(II) complexes with appended amide-glycinate groups were prepared to develop paramagnetic Co(II) chemical exchange saturation transfer (CEST) agents of reduced overall charge. Complexes with reduced charge and lowered osmolarity are important for their loading into liposomes and to provide complexes that are highly water soluble and well tolerated in animals. Co(L1) has two non-coordinating benzyl groups and two amide-glycinate pendants, whereas Co(L2) has two unsubstituted amide pendants and two amide-glycinate pendants on cyclam (1,4,8,11-tetraazacyclododecane). The H NMR spectrum of Co(L1) is consistent with a single cis-pendant isomer with both amide protons in the trans-configuration, as supported by an X-ray crystal structure. Co(L2) has a mixture of different isomers in solution, including the trans-1,4 and 1,8 pendant isomers. The Z-spectrum of Co(L1) shows one highly-shifted CEST peak, whereas Co(L2) exhibits six CEST peaks. Encapsulation of 40 mM Co(L1) in a liposome with osmotically-induced shrinking at 300 mOsm/L produces a liposomal CEST agent with saturation frequency offset of 3 ppm. Addition of the amphiphilic 1,4,7-triazacyclononane-based complex Co(L5) to the liposomal bilayer at 18 mM with Co(L1) encapsulated in the liposome at 50 mM changes the sign and increases the magnitude of the saturation frequency offset to -7.5 ppm at 300 mOsm/L.
制备了带有酰胺 - 甘氨酸基团的大环钴（II）配合物，以开发总电荷降低的顺磁性钴（II）化学交换饱和转移（CEST）剂。电荷降低且渗透压降低的配合物对于将其装载到脂质体中以及提供在动物体内高度水溶性且耐受性良好的配合物很重要。Co(L1) 有两个非配位苄基和两个酰胺 - 甘氨酸侧链，而 Co(L2) 在环胺（1,4,8,11 - 四氮杂环十二烷）上有两个未取代的酰胺侧链和两个酰胺 - 甘氨酸侧链。Co(L1) 的 (^1H) NMR 谱与单个顺式侧链异构体一致，两个酰胺质子均处于反式构型，X 射线晶体结构对此提供了支持。Co(L2) 在溶液中有不同异构体的混合物，包括反式 - 1,4 和 1,8 侧链异构体。Co(L1) 的 Z 谱显示一个高度位移的 CEST 峰，而 Co(L2) 显示六个 CEST 峰。将 40 mM 的 Co(L1) 包裹在脂质体中，在 300 mOsm/L 下通过渗透诱导收缩，产生一种脂质体 CEST 剂，其饱和频率偏移为 3 ppm。在脂质体双层中加入 18 mM 的两亲性 1,4,7 - 三氮杂环壬烷基配合物 Co(L5)，同时脂质体中包裹 50 mM 的 Co(L1)，在 300 mOsm/L 下改变了饱和频率偏移的符号并将其幅度增加到 -7.5 ppm。
