Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland.
Int J Mol Sci. 2021 Sep 10;22(18):9789. doi: 10.3390/ijms22189789.
Bent metallocene dichlorides (CpMCl, M = Ti, Mo, Nb, …) have found interest as anti-cancer drugs in order to overcome the drawbacks associated with platinum-based therapeutics. However, they suffer from poor hydrolytic stability at physiological pH. A promising approach to improve their hydrolytic stability is the formation of host-guest complexes with macrocyclic structures, such as cyclodextrins. In this work, we utilized nanoelectrospray ionization tandem mass spectrometry to probe the interaction of titanocene dichloride with β-cyclodextrin. Unlike the non-covalent binding of phenylalanine and oxaliplatin to β-cyclodextrin, the mixture of titanocene and β-cyclodextrin led to signals assigned as [βCD + CpTi-H], indicating a covalent character of the interaction. This finding is supported by titanated cyclodextrin fragment ions occurring from collisional activation. Employing di- and trimethylated β-cyclodextrins as hosts enabled the elucidation of the influence of the cyclodextrin hydroxy groups on the interaction with guest structures. Masking of the hydroxy groups was found to impair the covalent interaction and enabling the encapsulation of the guest structure within the hydrophobic cavity of the cyclodextrin. Findings are further supported by breakdown curves obtained by gas-phase dissociation of the various complexes.
弯曲茂金属二氯化物（CpMCl，M = Ti，Mo，Nb，…）作为抗癌药物引起了人们的兴趣，以克服与基于铂的治疗相关的缺点。然而，它们在生理 pH 值下的水解稳定性较差。提高其水解稳定性的一种很有前途的方法是与具有大环结构的主体-客体复合物形成，例如环糊精。在这项工作中，我们利用纳喷雾电离串联质谱法来探测二茂钛与β-环糊精的相互作用。与苯丙氨酸和奥沙利铂与β-环糊精的非共价结合不同，二茂钛和β-环糊精的混合物导致了被指定为[βCD+CpTi-H]的信号，表明相互作用具有共价性质。这一发现得到了由碰撞激活产生的钛化环糊精片段离子的支持。使用二甲基和三甲基β-环糊精作为主体，能够阐明环糊精羟基对与客体结构相互作用的影响。羟基的掩蔽被发现会损害共价相互作用，并使客体结构能够被包封在环糊精的疏水性空腔内。通过各种配合物的气相解离获得的分解曲线进一步支持了这一发现。
