Falconer, Robert Andrew; (2020) Synthesis Of Lipoamino Acid - Based Glycolipids For Drug Delivery. Doctoral thesis (Ph.D), UCL (University London College).

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Abstract

Many drug molecules are too hydrophilic to cross biological membranes and suffer from chemical and/or enzymatic degradation within the gastrointestinal tract. One approach to this problem is to conjugate such drugs to molecules that optimise their physicochemical properties. Conjugation of hpoamino acids to poorly absorbed peptides and drugs improves oral uptake due to enhanced membrane-like character and through increased protection from enzymatic degradation. The solubility of the resulting conjugates is often poor, however, in aqueous systems. This approach has been extended to incorporate a hydrophilic component, i.e. a glycosyl moiety, in an effort to improve solubility in aqueous media. In addition, the potential exists with such derivatives to exploit active transport systems, such as the sodium-dependent glucose transporter. A series of novel lipoamino acid-based glycohpids was synthesised, with functional groups suitable for both covalent and non-covalent conjugation to poorly absorbed drugs. The physicochemical properties of these compounds were varied through modifications to the sugar and lipid components and to the linkage between them (the glycosidic linkage). A series of /V-linked glycolipids was synthesised from p-glycosylamines, from glycosyl azides (using a modified Staudinger reaction) and from glycosyl isothiocyanates. A series of ^-linked glycolipids, with increased enzymatic stability, was synthesised using a set of novel Mitsunobu reaction conditions, following difficulties experienced (including low reactivity and disulphide formation) using other methods. Chemically and biologically stable C-linked glycolipids were prepared using a glycosyl radical-based reaction. In addition, novel C-linked glycohpids were successfully prepared directly from their «S-linked isosteres using a Ramberg-Backlund rearrangement. Preliminary experiments demonstrated improved oral absorption of piperacillin, a poorly absorbed p-lactam antibacterial, when administered as a novel drug-glycohpid ionic complex. In addition, the abihty to form particulate systems per se and in conjunction with conventional Hposomes was demonstrated by these glycohpids, with further potential apphcations for drug and peptide dehvery.

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