Synthesis of azido- functionalized cyclodextrin derivatives for bio-orthogonal ligations
Cyclodextrins (CD) are naturally occurring cyclic oligomers of D-glucose, which have been widely used in pharmaceuticals for their remarkable ability to form inclusion complexes with drugs, thus increasing their water solubility and bioavailability. Encapsulation of drugs usually results in a 1:1 stoichiometry complex of drugs and CD. However, in order to enhance the drug loading capacity and fluorescently track CD when injected in animals, azido-functionalised CD derivatives as multivalent molecules would be valuable. The CD scaffold provides multivalent character and the azido-groups enable bio-orthogonal ligations which can be used for cell labelling and imaging. CDs have been employed as the core for the synthesis of dendritic molecules. Dendrimers are highly branched symmetrical molecules having interior pockets which can encapsulate drug molecules. The dendrimers are highly dominated by the functionalities on their outer surface, thus leading to a multivalent system. CD incorporated dendrimers can encapsulate drug molecules irrespective of their size with high drug loading. In this summer training project, we embarked on the synthesis of per-azido-derivative of β-cyclodextrin (β-CD) following reported procedures from the literature. The synthesis of azido-substituted β-CD was achieved in a two step reaction sequence. In the first step, the seven primary hydroxyl groups were substituted by iodine atoms. Treating β-CD (1), dissolved in DMF, with I2 and Ph3P at 70°C gave the per-6-iodo-cyclodextrin (2), as reported by Defaye and Gadelle. In the second step, the heptaiodo-β-CD (2) was dissolved in DMF and treated with NaN3 to give per-6-azido-β-cyclodextrin (3), following a publication from Stoddart and co-workers. A portion of the per-azido-β-cyclodextrin was per-acetylated by dissolving (3) in pyridine and treating it with acetic anhydride. The peracetyl heptaazido-β-CD derivative was purified by silica gel column chromatography. All these compounds were characterised by mass spectrometry, thin layer chromatography, and nuclear magnetic resonance (1H and 13C NMR) spectroscopy.