Beta Cyclodextrin Modifications as Organocatalysts and Cyclodextrin-Halo Protein Complex for Targeted Drug Delivery

Abstract

Cyclodextrin (CD) is a type of cyclic oligosaccharide that commonly contains 6 to 8 glucopyranose units, forming a hollow truncated cone-like structure with a hydrophilic outer surface and a hydrophobic inner cavity. Due to its unique structure and easy complexation with many biomolecules, it has played a critical role in water solubility improvement, slow release, and transportation of hydrophobic molecules like dyes and drugs. Historically, raw beta cyclodextrin has been used as a catalyst for some organic reaction under aqueous conditions and as water solubility booster for drugs. Many current drug formulations often include cyclodextrin to increase the solubility and bioavailability of the active ingredients. However, natural beta-cyclodextrin has its limitations in water solubility and target cell specificity. To address these limitations, many derivatives of cyclodextrin have been synthesized for specific applications. However, each modification of cyclodextrin requires a different synthesis method to install the exact functional group required for performance improvement of modified cyclodextrin. To create more diverse modifications of beta cyclodextrin with consistent reaction, Cu1 azide-alkyne Huisgen cycloaddition (click) reaction was explored with 6A-Azido-6A-deoxy-beta-cyclodextrin which can be an intermediate clickable beta cyclodextrin for click reaction. Click chemistry provides a highly specific and regioselectivity method of modification for cyclodextrin, as it requires an azido and an alkyne group which are rare functional groups in natural organic molecules. Many more modifications of beta cyclodextrin can become possible through simple click chemistry. To investigate the feasibility of this method of beta-cyclodextrin modification, beta-cyclodextrin derivatives with small molecules connected by click chemistry were used to examine the potential of organic catalytic activity and improved delivery potential of beta cyclodextrin. For organic catalytic activity screening, the clickable beta cyclodextrin was attached with some amino acid derivatives to observe the effects of cyclodextrin-amino acid conjugate. Cyclodextrin-amino acid (CD-AA) complex conjugates were tested with a Wieland–Miescher ketone synthesis reaction (WMK) for the organocatalytic potential of clicked beta-cyclodextrin derivative. Beta-cyclodextrins clicked with halogen containing small molecules were investigated for a potential direct connection to HaloTag protein at the surface of cell membrane which could open the door for many new utilities of CD-peptide complexes including targeted delivery of drug molecules.