Synthesis of Glycoconjugates and their Analogs for the Study of Biological Systems

ABSTRACT The project was focussed on the development of three main topics: a) trehalose mimics as trehalase inhibitors, b) synthesis of multivalent glycoconjugates and c) synthesis of glycosylated Pluronic block copolymers. a) Trehalose mimics as trehalase inhibitors Trehalase (α-glucoside-1-glucohydrolase, EC 3.2.1.28) is a specific glycosidase that catalyzes the hydrolysis of trehalose (α-D-glucopyranosyl-α-D-glucopyranoside) to the two constituent glucose units. This disaccharide is found in many organisms, but is absent in mammals. In insects, trehalose hydrolysis by trehalase is fundamental in various physiological processes. Given these premises, insect trehalases are attractive targets for the search of inhibitors as potential novel and selective insecticides. The aim of the project is the design, synthesis and in vitro and in vivo biological evaluation of some trehalose mimics (iminosugars or polyhydroxylated pyrrolizidine alkaloids) as selective insect trehalases inhibitors. b) Synthesis of multivalent glycoconjugates Recognition processes between glycans and their receptors are of paramount relevance in several biological phenomena, both in physiological and in pathological conditions. Moreover, most often these binding events occur in a multivalent and cooperative manner. In order to better understand these phenomena, dendrimers and dendrons have been developed to provide multivalent glycoconjugates. The aim of the project is the design and synthesis of new hetrobifunctional dendrons for carbohydrates multivalent presentation, and the study of synthetized glycoconjugates interactions with specific proteins. c) Synthesis of glycosylated Pluronic block copolymers Polymer-based nanotechnology became one of the most attractive and fast growing areas of pharmaceutical research. One promising example of such polymer nanomaterials is represented by a class of Pluronic block copolymers. In aqueous solutions, at concentrations above critical micelle concentration, these copolymers self-assemble into micelles. In application to anticancer chemotherapy, low molecular mass drugs encapsulation in micelles can diminish drug extravasation into normal tissues and provide for a passive drug targeting to tumors via the enhanced permeability and retention (EPR) effect. In order to gain also an active targeting effect on Pluronic micelles, I have been working on the design and synthesis of new glycosylated Pluronic block copolymers for antitumor drug delivery.