“Click” Saccharide/-Lactam Hybrids for Lectin Inhibition Claudio Palomo,* ,† Jesus M. Aizpurua,* ,† Eva Balentova ´, Itxaso Azcune, J. Ignacio Santos, Jesu ´s Jime ´ nez-Barbero,* ,‡ Javier Can ˜ ada, and Jose ´ Ignacio Miranda Departamento de Quı ´mica Orga ´nica-I, UniVersidad del Paı ´s Vasco, Joxe Mari Korta R&D Center, AVda, Tolosa-72, 20018 San Sebastia ´n, Spain, and Centro de InVestigaciones Biolo ´gicas, CSIC, Ramiro de Maeztu-9, 28040 Madrid, Spain jesusmaria.aizpurua@ehu.es Received March 21, 2008 ABSTRACT Hybrid glycopeptide -lactam mimetics designed to bind lectins or carbohydrate recognition domains in selectins have been prepared according to a “shape-modulating linker” design. This approach was implemented using the azide-alkyne “click” cycloaddition reaction, and as shown by NMR/MD experiments, binding of the resulting mimetics to Ulex Europaeus Lectin-1 (UEL-1) occurred after a “bent-to-extended” conformational change around a partially rotatable triazolylmethylene moiety. Hybrid constructs 1 of natural or unnatural molecular entities are an important source of molecular diversity. This approach often takes advantage of the inherent biological activity of all or part of the components embodied in the conjugates. For a successful design, however, it is not enough to decide which fragments to incorporate into the hybrid but also to know where to place them. Therefore, a precision crafting is often necessary to generate hybrids permitting an efficient molecular recognition of each and every bioactive fragment, especially when the “rigid scaffold” design is used (Figure 1). We would like to outline here the advantages of an alternative “shape-modulating linker” design which provides partially flexible hybrids by connecting their rigid(ified) components with rotatable covalent bonds. As an example † Universidad del Paı ´s Vasco. ‡ Centro de Investigaciones Biolo ´gicas, CSIC. (1) For reviews, see: (a) Mehta, G.; Singh, V. Chem. Soc. ReV. 2002, 31, 324–334. (b) Tietze, L.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int. Ed. 2003, 42, 3996–4028. (c) Meunier, B. Chem. ReV. 2008, 104, 69– 77. Figure 1. Semirigid hybrids: “shape-modulating linker” design. ORGANIC LETTERS 2008 Vol. 10, No. 11 2227-2230 10.1021/ol8006259 CCC: $40.75  2008 American Chemical Society Published on Web 05/09/2008