Factors influencing the pKa of ligated amines and the syn/anti isomerization in cysteine-based Re(V)=O(N2S2) radiopharmaceutical analogues as revealed by a novel dominant tautomer in the solid state
Factors influencing the pKa of ligated amines and the syn/anti isomerization in cysteine-based Re(V)=O(N2S2) radiopharmaceutical analogues as revealed by a novel dominant tautomer in the solid state
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DOI：
10.1021/ic9906398
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发表时间：
1999-11-15
影响因子：
4.6
通讯作者：
Marzilli, LG
中科院分区：
文献类型：
--
作者：
Hansen, L;Lipowska, M;Marzilli, LG
有效的放射性药物设计需要了解在生理pH下导致一种异构体物质处于一种电离状态的因素。因此，对于典型的M（V）O（N2 S2）（M = Tc-99 m，Re-186/188）试剂，所有pK（a）值必须在6-9的范围之外。特别地，对于肾剂的快速清除所需的侧羧基必须相对于N2 S2配体平面仅与氧代配体顺式或仅反式。用于制备放射性药物的单酰胺-单胺-二硫醇（单酰胺-单胺= MAMA）配体通常与一个类似于6-7（仲胺）的核心配体pK（a）以及顺式和反式异构体形成M（V）O（N2 S2）络合物。我们设计了一种新的MAMA配体，巯基乙酰胺-乙烯-半胱氨酸（MAECH（5）），其吸电子羧基与NH基团仅通过两个键分开。仅分离出syn-ReO（MAECH（2））。[AsPh 4]（+）盐晶体中单阴离子顺式-[ReO（MAECH）]（-）的结构揭示了互变异构体（t（2））的CO2 H与CO2 H和胺N-之间的晶格H-键合以及相邻t（2）阴离子的C=O;这种相互作用导致t（2）优先结晶。然而，在顺式[ReO（MAECH）]（-）的水溶液中，主要的单阴离子互变异构体（t（1））具有CO2-和胺NH，如H-1 NMR和共振拉曼光谱所示。由于负CO2-的吸电子和静电效应的抵消，NH的酸性较低;因此，syn-[ReO（MAECH）]（-）的pK（a）值（6.0 +/- 0.1）与羧基和NH不接近的区域异构体syn-[ReO（CACAH）]（-）的pK（a）值相似（CACAH（5）=半胱氨酸-乙酰基-半胱胺）。我们的研究结果表明，羧基的位置也影响顺/反平衡。在顺式-[ReO（MAECH）]（-）中羧基与褶皱环的连接似乎有利于顺式异构体，并增加顺式/反式异构化的速率。ReO（CACAH（2）），羧基连接到由酰胺供体锚定的较不起皱的螯合环上，形成为顺/反异构体的非互变大致相等的混合物。因此，为了使MAMA配体形成pK（a）< 6的顺式异构体，必须将其设计为在NH基团附近具有不可电离的吸电子基团，并且在褶皱环上具有侧羧基。
Efficient radiopharmaceutical design demands an understanding of factors that lead to one isomeric species in one ionization state at physiological pH. Thus, all pK(a) values must be outside the range of 6-9 for the typical M(V)O(N2S2) (M = Tc-99m, Re-186/188) agents. The pendant carboxyl group needed for rapid clearance of renal agents in particular must be either only syn or only anti to the oxo ligand with respect to the N2S2 ligand plane. Monoamide-monoamine-dithiol (monoamide-monoamine = MAMA) ligands useful in preparing radiopharmaceuticals typically form M(V)O(N2S2) complexes with one core ligand pK(a) of similar to 6-7 (secondary amine) and with both syn and anti isomers. We designed a new MAMA ligand, mercaptoacetamide-ethylene-cysteine (MAECH(5)), with the electron-withdrawing carboxyl group separated by only two bonds from the NH group. Only syn-ReO(MAECH(2)) was isolated. The structure of the monoanion syn-[ReO(MAECH)](-) in the crystal of a [AsPh4](+) salt reveals lattice H-bonding between the CO2H of a tautomer (t(2)) with a CO2H and an amine N- and the C=O of a neighboring t(2) anion; this interaction results in preferential crystallization of t(2). However, in aqueous solutions of syn-[ReO(MAECH)](-), the predominant monoanionic tautomer (t(1)) has a CO2- and an amine NH, as indicated by H-1 NMR and resonance Raman spectra, The endo-NH configuration favored in M(V)O(N2S2) complexes places the NH and CO2- groups in t(1) spatially close. The NH is less acidic due to the cancellation of the electron-withdrawing and electrostatic effects of the negative CO2-; as a result, syn-[ReO(MAECH)](-) has a pK(a) value (6.0 +/- 0.1) similar to that of the regioisomer syn-[ReO(CACAH)](-) in which the carboxyl group and the NH are not close (CACAH(5) = cysteine-acetyl-cysteamine). Our results suggest that the carboxyl group position also influences the syn/anti equilibrium. Attachment of the carboxyl group to a puckered ring in syn-[ReO(MAECH)](-) appears both to favor the syn isomer and to increase the rate of syn/anti isomerization. ReO(CACAH(2)), with a carboxyl group attached to a less puckered chelate ring anchored by the amido donor, formed as a noninterconverting roughly equal mixture of syn/anti isomers. Thus, for a MAMA ligand to form a syn isomer with a pK(a) < 6, it must be designed with a nonionizable electron-withdrawing group near the NH group and a pendant carboxyl on a puckered ring.