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36 Synthesis and Biological Applications of Glycoconjugates, 2011, 36-63 Multivalent Glycocalixarenes Francesco Sansone, Gabriele Rispoli, Alessandro Casnati * and Rocco Ungaro Olivier Renaudet and Nicolas Spinelli (Eds) All rights reserved - © 2011 <strong>Bentham</strong> <strong>Science</strong> Publishers CHAPTER 3 Dip.to di Chimica Organica e Industriale, Università degli Studi, Parco Area delle Scienze 17/A, 43124 Parma, Italy Abstract: Calixarenes, the cyclic oligomers obtained by condensation of phenols or resorcinols with aldehydes, are ideal scaffolds for the construction of multivalent glycosylated ligands with unique properties. Thanks to the possibility that we can vary their size, valency and conformation and finely tune the topology of the saccharide units in the space, a wide variety of glycocalixarenes could have been prepared in the last 15 years. In this account, after a brief review on the basic chemistry of calixarenes, we will focus the attention on the most convenient methodologies used so far for the synthesis of glycocalixarenes and on their aggregation and biological properties. Glycocalixarenes often show, in fact, an impressive ability in the recognition and inhibition of carbohydrate binding proteins (lectins) disclosing remarkable multivalent effects. The amphiphilic character, due to the simultaneous presence of highly hydrophilic saccharide units and of a lipophilic aromatic backbone, confers to glycocalixarenes a marked tendency to self-aggregate in water solution. A quite unique peculiarity of these glycoclusters is related to their combined ability to firmly bind small organic molecules and to strongly and selectively interact with lectins, which makes them ideal candidates for tomorrow’s site-specific drug-delivery systems. Other important biological functions have been envisaged to be influenced by the multivalency of glycocalixarenes which span gene-delivery, inhibition of tumor cell migration and proliferation to stimulation of the immunogenic system. Keywords: calixarenes, multivalent effect, lectin inhibition, tumor targeting, cell transfection. INTRODUCTION Saccharides are not only fundamental chemical energy sources and structurally important elements, but also play a fundamental role in a wide range of biological processes [1]. Many important physiological and pathological events, such as intercellular communication, cell trafficking, immune response, infections by bacteria and viruses, growth and metastasis of tumour cells, occur due to the recognition of carbohydrate moieties by the corresponding cell protein receptors. These proteins, which lack immune and enzymatic activity, are known as lectins [2]. The communication between carbohydrates and lectins is so specific that it is frequently referred to as Sugar Code [3]. Interestingly, lectins are frequently characterized by the presence of equivalent binding sites for carbohydrates so that, although the affinity of a single saccharide unit for the receptor is usually low, the simultaneous presentation of several proper and identical glycoside units to lectins, ensures a strong and specific interaction. This phenomenon has been named glycoside cluster effect [4], a particular and widely spread case of multivalency [5], and the multivalent neoglycoconjugates which are synthesised to interfere with all these important phenomena are also called glycoclusters. MULTIVALENCY Multivalency is the ability of a particle (or molecule) to bind another particle (or molecule) via multiple, and simultaneous noncovalent interactions (Fig. 1) [5]. The valency is the number of ligating functionalities of the same or similar type connected to each of these entities. Even when the single interactions are rather weak (with dissociation constants Kd in the mM range), thanks to the simultaneous operation of multiple attractive interactions, multivalency is usually characterised by high thermodynamic (Kd in the subnanomolar range) and kinetic stability. Nowadays it is clearly ascertained that multivalency controls many important biological processes [1, 5]. Nature exploits multivalency to convert relatively weak interactions (e.g. carbohydrate-protein interactions) into strong and specific recognition events. It is therefore clear why, in the latest years, Supramolecular Chemistry, the chemistry of noncovalent interactions, became more *Address correspondence to Alessandro Casnati: Dip.to di Chimica Organica e Industriale, Università degli Studi, Parco Area delle Scienze 17/A, 43124 Parma, Italy; E-mail: casnati@unipr.it
Multivalent Glycocalixarenes Synthesis and Biological Applications of Glycoconjugates 37 and more interested in applying the multivalency concepts to the recognition of biological important molecules [6-8] and to nanotechnology [9]. Interestingly, supramolecular systems, often being simpler than the natural ones, can help the understanding and quantitative description of the multivalent effect [10]. Although multivalent ligands may remarkably differ for their topology (Fig. 2), they generally consist of a main core, called scaffold, which bears several covalent connections, linkers or spacers, to the peripheral ligating (binding) units. In principle, any multivalent scaffold can be used, from those having low valency such as benzene derivatives, monosaccharides, transition metal complexes, azamacrocycles, cyclodextrins or calixarenes to high valency ones such as dendrimers, polymers, peptoids, proteins, micelles, liposomes, and self-assembled monolayers (SAMs) on nanoparticles or surfaces (Fig. 2). Figure 1: a) Monovalent and b) multivalent complex formation. Figure 2: Different types of multivalent ligands. a) 1-D finite and linear arrangement; b) polymers/peptoids; c) 2-D cyclic/macrocyclic structures; d) 2-D self-assembled monolayers (SAM) on Au/quartz; e) 3-D cavity containing scaffolds (cyclodextrins/calixarenes); f) nanoparticles/dendrimers/liposomes. A quite useful approach to describe multivalent binding and based on the additivity of the free energies [11, 12] was proposed, where the standard binding free energy for the multivalent interaction G ° multi is G ° multi = nG ° mono + G ° interaction (eq. 1) where G ° mono is the standard binding free energy of the corresponding monovalent interaction, n is the valency of the complex and G ° interaction is the balance between favourable and unfavourable effects of tethering. A more qualitative but often rather helpful parameter, named or enhancement factor, was introduced by Whitesides [5]. It is defined as = Kmulti/Kmono (eq. 2) where Kmulti and Kmono are the association constants for the multivalent and monovalent complexes, respectively.
Page 2 and 3: Synthesis and Biological Applicatio
Page 4 and 5: CONTENTS Foreword i Preface ii List
Page 6 and 7: FOREWORD Attachment of carbohydrate
Page 8 and 9: List of Contributors Didier Boturyn
Page 12 and 13: Bacterial Lectins and Adhesins Synt
Page 14 and 15: Ligands for FimH Synthesis and Biol
Page 18 and 19: 38 Synthesis and Biological Applica
Page 20 and 21: Solving Promiscuous Protein Carbohy
Page 26 and 27: Monovalent and Multivalent Glycocon
Page 28 and 29: 116 Synthesis and Biological Applic
Page 36 and 37: Oligonucleotide-Carbohydrate Conjug
Page 38 and 39: Glycoliposomes and Metallic Glycona
Page 42 and 43: Chemoselective Glycosylation Techni
Page 44 and 45: Glycosidases in Synthesis of Glycom
Page 52 and 53: A Synthesis and Biological Applicat
Page 54: Index Synthesis and Biological Appl

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