[a] 6-Mono-and 6-multi-S-nitroso-b-cyclodextrins (SNObCDs) were prepared from their corresponding thiols (SHbCDs) and characterized in detail for the first time in terms of their conformational preferences and SNO content, thermal and photochemical stability, their ability to encapsulate guest molecules, and their cell toxicity and permeation. The prevalence of gauche-trans (gt) over gauche-gauche (gg) conformations (with respect to rotation about the C5ÀC6SH bond and, hence, to the bCD cavity) and the presence of syn-to-anti equilibria (with respect to the C6S-NO configuration) in SNO-CDs and in a reference compound, S-nitrosoglutathione (GSNO), were suggested by 1 H and 15 N NMR spectroscopy. Quantum mechanical calculations indicated that the gt conformations indeed prevail in mono-SH-bCD and mono-SNO-bCD, whereas a blend of gt/gg conformations prevail in per-SH-bCD and per-SNO-bCD. This reflected the presence of two potentially dissimilar SNO groups with diverse stabilities toward NO release and propensities for forming interglucose S À S bonds. Moreover, syn conformers were energetically preferred in all cases. Mono-SNO-bCD is water soluble, thermally more stable than GSNO, and undergoes photocontrolled NO release. Furthermore, the CD cavity is available for guest encapsulation without noticeable perturbation of the SNO functionality whilst hosting, for example, the chemotherapeutic tamoxifen. Nitrosation of per-SH-bCD to form per-SNO-bCD was found to compete with SNO decomposition and disulfidebridge formation, thereby resulting in an average of 5.2 SNO groups instead of 7. Upon isolation, SNO-CDs, as well as GSNO, suffer a small additional loss of SNO groups, mostly to afford disulfides. Multi-SNO-bCD is soluble in DMSO and displays better thermal stability than GSNO and cell permeability. Both SNO-CDs were found to be chemically non-toxic to cells at high incubation concentrations (> 200 mm); thus, they represent a potentially new family of bimodal drug-delivery systems.
Summaryβ-Cyclodextrin (β-CD) dimers have been prepared using the bioorthogonal Staudinger ligation for the first time. In addition to a known linker, methyl 2-(diphenylphosphanyl)terephthalate, a doubly active linker was specifically developed that enabled connection of two β-CD units in a single step and in aqueous/organic media, under mild conditions and with good yields. A three-carbon spacer between the β-CD torus and the azido group was required for facile dimer formation. The products, as studied by NMR spectroscopy, were found to adopt closed conformations by intramolecular self-inclusion. On the other hand, association via intermolecular binding was also observed in aqueous solution, confirmed by DOSY NMR experiments. Despite self-inclusion, the β-CD cavities were capable of guest encapsulation, as shown by titration experiments: the binding constant with 1-adamantylamine was similar to that of natural β-CD. Theoretical calculations for isolated molecules (PM3 level of theory) and in the presence of solvent [water, PM3(COSMO)] as well as DFT calculations suggested that the compounds prefer to adopt conformations which bring the phenyl groups either inside the β-CD cavity (inclusion) or over its narrow side (vicinal). Thus, Staudinger ligation could be the method of choice for linking CDs exhibiting (i) ease of preparation in aqueous media, in short steps, under mild conditions and in good yields, (ii) satisfactory aqueous solubility and independent binding capacity of the cavities.
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