Abstract
Bent metallocene dichlorides (Cp2MCl2, 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 + Cp2Ti–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.
Highlights
Good solubility and stability in a physiological aqueous environment are essential prerequisites of a pharmaceutically active compound in order to develop its therapeutic activity
In contrast to β-cyclodextrin complexes with phenylalanine and oxaliplatin, separation of the host and guest structures was not observed as neither the intact β-cyclodextrin nor free titanocene-derived ions (e.g., [Cp2 Ti(OH)]+ ) were detected and all fragment ions were found to contain titanium. These results indicate that the interaction of titanocene dichloride with cyclodextrin differs from the situation observed for the phenylalanine and oxaliplatin guest species
Experiments with phenylalanine and oxaliplatin demonstrated the ability of elec3
Summary
Good solubility and stability in a physiological aqueous environment are essential prerequisites of a pharmaceutically active compound in order to develop its therapeutic activity Within this context, low bioavailability due to high hydrophobicity, fast degradation, or deactivation as a result of rapid reaction with unspecific targets represent a continuous challenge in drug formulation [1,2]. Cisplatin exhibits a planar structure with a platinum(II) coordination center surrounded by two ammine and two chloride ligands in cis configuration (Figure 1) [4]. It is widely used in cancer treatment but suffers from severe side-effects due to its toxicity and accruing drug resistance [5]. Transition metal centered bent metallocenes emerged as a promising alternative to platinum-based drugs [5]
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