Polymethylated DOTA ligands. 1. Synthesis of rigidified ligands and studies on the effects of alkyl substitution on acid-base properties and conformational mobility.
Polymethylated DOTA ligands. 1. Synthesis of rigidified ligands and studies on the effects of alkyl substitution on acid-base properties and conformational mobility.
复制标题
多甲基化 DOTA 配体。
作者：
R. Ranganathan;R. Pillai;N. Raju;Helen Fan;Hanh Nguyen;M. Tweedle;J. Desreux;V. Jacques
这项工作描述了新的多甲基化的大环配体的磁共振成像的潜在利益的合成和构象特性。（2S，5S，8 S，11 S）-2，5，8，11-四甲基-1，4，7，10-四氮杂环十二烷（M4 cyclen）是由（2S）-1-苄基-2-甲基氮丙啶经环四聚、催化氢化制得。配体M4 DOTA，[（2S，5S，8 S，11 S）-4，7，10-三-羧甲基-2，5，8，11-四甲基-1，4，7，10-四氮杂环十二烷-1-基]乙酸和M4 DOTMA，（R）-2-[（2S，5S，8 S，11 S）-4，7，10-三-（（R）-1-羧乙基）-2，5，8，11-四甲基-1，4，7，10-四氮杂环十二烷-1-基]丙酸，在Na（2）CO（3）存在下，通过羧烷基化M4 cyclen制备。当加入羧基臂时，如果NaHCO（3）是酸清除剂，则以良好的产率获得三乙酸配体M4 DO 3A，[（2S，5S，8 S，11 S）-4，7-双-羧甲基-2，5，8，11-四甲基-1，4，7，10-四氮杂环十二烷-1-基]乙酸，而没有痕量的M4 DOTA。在相同条件下，大环草胺以82%的产率生成M4 DOTA。cyclen和M4 cyclen的反应性之间的差异被分配到高碱度的取代的四胺估计通过NMR滴定。M4 DOTA和M4 DOTMA在H（4）L或H（6）L（2+）形式下的一维和二维（1）H和（13）C NMR谱被解释为由两个伸长的几何构型之间的缓慢交换引起，其中甲基取代基位于两个可能的赤道状位置之一，靠近或远离羧基臂。轴向位置在空间上过于拥挤，不能被甲基占据。DOTMA，（R）-2-[4，7，10-三-（（R）-羧乙基）-1，4，7，10-四氮杂环十二烷-1-基]丙酸，也采用拉长的构象，呈H（6）L（2+）形式。多甲基化配体的硬化允许详细的NMR分析，这不能在母体未取代的配体DOTA上进行。
This work describes the synthesis and the conformational properties of new polymethylated macrocyclic ligands of potential interest for magnetic resonance imaging. M4cyclen, (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane, was obtained by cyclotetramerization of (2S)-1-benzyl-2-methylaziridine followed by catalytic hydrogenation. The ligands M4DOTA, [(2S,5S,8S,11S)-4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl- 1,4,7,10-tetraazacyclododecan-1-yl]acetic acid, and M4DOTMA, (R)-2-[(2S,5S,8S,11S)-4,7,10-tris-((R)-1-carboxyethyl)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]propionic acid, were prepared by carboxyalkylation of M4cyclen in the presence of Na(2)CO(3). The triacetic ligand M4DO3A, [(2S,5S,8S,11S)-4,7-bis-carboxymethyl-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid, was obtained in good yields without traces of M4DOTA if NaHCO(3) was the acid scavenger when adding the carboxylic arms. In the same conditions, cyclen yielded M4DOTA in 82% yield. The difference between the reactivity of cyclen and M4cyclen is assigned to the high basicity of the substituted tetraamine as estimated by NMR titration. The one- and two-dimensional (1)H and (13)C NMR spectra of M4DOTA and M4DOTMA in the H(4)L or H(6)L(2+) forms are interpreted as arising from a slow exchange between two elongated geometries in which the methyl substituents are in one of the two possible equatorial-like positions, either close to or away from the carboxylic arms. The axial-like positions are sterically too crowded and cannot be occupied by the methyl groups. An elongated conformation is also adopted by DOTMA, (R)-2-[4,7,10-tris-((R)-carboxyethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propionic acid, in the H(6)L(2+) form. The rigidification of the polymethylated ligands allows a detailed NMR analysis that cannot be carried out on the parent unsubstituted ligand DOTA.