Cyclodextrin/imatinib complexation:: Binding mode and charge dependent stabilities
Cyclodextrin/imatinib complexation:: Binding mode and charge dependent stabilities
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DOI：
10.1016/j.ejps.2006.10.008
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发表时间：
2007-02-01
影响因子：
4.6
通讯作者：
Noszal, Bela
中科院分区：
文献类型：
--
作者：
Beni, Szabolcs;Szakacs, Zoltan;Noszal, Bela
使用质子磁共振波谱 (H-1 NMR)、相溶解度、pH 电位测定和电喷雾电离质谱 (ESI-MS) 技术研究了抗癌药物伊马替尼与 β-环糊精 (CD) 和随机甲基化 β-CD (RAMEB) 的各种质子化形式的主客体相互作用。相溶解度分析显示与β-CD呈A(L)型图，这表明形成了1:1的包合物。通过水溶液中的电位测定法和气相中的 ESI-MS 证实了 1:1 化学计量。测定了 β-CD 和 RAMEB 的中性、单阳离子、二阳离子和三阳离子形式的伊马替尼的电荷特异性稳定常数。 β-CD 复合物的稳定性在单质子化形式下显示出意想不到的最小值，而 RAMEB 则随着客体电荷的增加而逐步降低。所选伊马替尼质子化物质的 1:1 复合化学计量和稳定常数通过 H-1 NMR 滴定进行验证。进行二维旋转框架核欧沃豪塞效应光谱（ROESY）实验来鉴定相互作用的主客体部分。观察到的 ROESY 交叉峰表明伊马替尼的几个芳香氢和 P-CD 质子之间的空间邻近性，表明包合是通过伊马替尼的苯甲酰胺环的调节而发生的。 (c) 2006 Elsevier B.V. 保留所有权利。
Host-guest interactions in various protonation forms of the anticancer drug imatinib with beta-cyclodextrin (CD) and randomly methylated beta-CD (RAMEB) have been investigated using techniques of proton magnetic resonance spectroscopy (H-1 NMR), phase solubility, pH-potentiometry and electrospray ionization mass spectrometry (ESI-MS). Phase-solubility analysis showed A(L)-type diagram with beta-CD, which suggested the formation of 1:1 inclusion complexes. The 1:1 stoichiometry was confirmed by potentiometry in aqueous solution and by ESI-MS in the gas phase. Charge-specific stability constants of the neutral, mono-, di-, and tricationic forms of imatinib were determined for both the beta-CD and RAMEB. Stability of the beta-CD complexes shows an unexpected minimum at the monoprotonated form, while a stepwise decrease with increasing guest charge was observed for RAMEB. The 1:1 complex stoichiometry and stability constants of selected imatinib protonation species were verified by H-1 NMR titrations. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out to identify the interacting host-guest moieties. The observed ROESY cross-peaks indicated spatial proximities between several aromatic hydrogens of imatinib and P-CD protons, revealing that the inclusion occurs by accommodation of the benzamide ring of imatinib. (c) 2006 Elsevier B.V. All rights reserved.