Improved syntheses of bis(β-cyclodextrin) derivatives, new carriers for gadolinium complexes

Abstract

In the last decade a number of reports have been published on the synthesis and characterization of bridged cyclodextrin dimers (bis-CDs) connected with linkers of different lengths and structures. These dimers, having two hydrophobic cavities in close proximity, display much higher binding affinities and molecular selectivities than parent CDs, forming stable supramolecular adducts. We describe new synthetic protocols for the preparation of bis(β-CDs) bearing 2–2′, 3–3′ and 6–6′ bridges. Some of the critical steps were carried out either under high-intensity ultrasound (US) or microwave (MW) irradiation. Bis(β-CDs) containing 6–6′ ureido- and thioureido-bridges were prepared in high yields by a MW-promoted aza-Wittig reaction using polymer-bound triphenylphosphine, while those containing 2,2′ and 3,3′ bridges were prepared from mono-alkenyl β-CDs by the cross-metathesis reaction (homodimerization) in the presence of 2^nd-generation Grubbs catalyst under sonochemical conditions. By these improved protocols CD dimers could be obtained in gram amounts to prepare stable adducts of bis-CDs with contrast agents (CAs) containing gadolinium(III) chelates. In the case of Gd(III) chleate “G-1” the inclusion complexes were found to be 2 to 3 orders of magnitude more stable than that formed by β-CD (K_ass = 4.3 × 10⁴ M⁻¹vs 8.0 × 10² M⁻¹). Relaxivity increased as well by factors of 3 and 4, viz. from 9.1 mM⁻¹ s⁻¹ (β-CD) to 27.7 and 35 mM⁻¹ s⁻¹.