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The outstanding physio-pathological role played by integrin receptors in living subjects motivates the enormous interest shown by scientists worldwide for this topic. More than twenty years of research has spanned across the structural and functional elucidation of these proteins and over their antagonism-based biomedical applications. The proof-of concept stage, aimed at identifying potent inhibitors, covered a decade of studies, and paved the way for a more advanced era of research where these antagonist molecules were thrown into the deep end of applicative studies. This review intends to summarize the major efforts conducted thus far and focuses on the design, synthesis and biomedical applications of cyclic RGD-containing alpha(v)beta(3) integrin antagonists, in both their small and macromolecular formats. In particular, Chapters 1 and 2 offer a comprehensive outlook on the rational basis for the design of integrin inhibitors, Chapter 3 chronicles the biological and medical applications of monofunctional RGD integrin ligands both in their monomeric and multimeric asset, and Chapter 4 illustrates the potential of RGD-based multifunctional systems in molecular medicine.

Casiraghi et al.Giovanni Casiraghi was born in Monza, Italy, in 1939 and took his laurea degree in Chemistry in the University of Pavia. After postdoctoral work at the same University with Professor S. Pietra (1965Pietra ( -1968), he joined the Department of Organic Chemistry at University of Parma. In 1971 he became an Assistant Professor and in 1980 an Associate Professor of Organic Chemistry. In 1986 he was promoted to a Professorship in Organic Chemistry and, in the same year, he transferred to the University of Sassari. In 1991 he returned to the University of Parma, joining the Faculty of Pharmacy (Pharmaceutical Department) where he was appointed to the Chair in Organic Chemistry. Topics he is now interested in include asymmetric organic synthesis and the design and implementation of novel synthetic strategies to densely functionalized compounds of biological interest, including carbohydrate mimics, amino acids, modified nucleosides, glyco-and nucleoporphyrins.Franca Zanardi was born in S. Secondo, Parma, Italy, in 1968. She studied Chemistry at the University of Parma where she received her laurea degree in 1993. Since 1992 she has been working under the OBn OBn 19 20 21 3 Key: (a) MeN02, DBU; (b) Net oxidation; (c) EtSH, HCI; then NaH, BnBr, DMF; then Mel, Na2C03; (d) (Et0)2P(0)CH(NHCbz)C02Me, NaH, CH2CI2; (e) H2, Pd/C; (f) H2, Pd(OH)2; then Dowex H*. MeOH. 3 Key: (a) HCN2C02Et; (b) Ao20, pyridine; then Rh2(AcO)4; (c) NH2NH2, MeOH; (d) Mn02, CHCI3; then TBAF, THF; (e) MCPBA, CHCI3;then AcOH; then NH4OH; (f) Rh2(AcO)4, C6H6; (g) TFA; then NH4OH.

An expedient and practical in-solution synthesis of three new 4-aminoproline-based arginine-glycine-aspartate integrin binders--compounds 15, 17 and 19--is presented. Two candidates carrying exposed azide and amine functional points were further advanced to trimeric platform 21 as well as fluorescein- and DOTA-conjugates 23 and 25. The new compounds were assayed for their binding affinity towards human alpha(V)beta3 and alpha(V)beta5 integrin receptors. Both monomeric candidates and covalent conjugates revealed potent ligand competence for the alpha(V)beta3 receptor in the one-digit nanomolar range (IC50 alpha(V)beta3 = 0.2-8.0 nM; IC50 alpha(V)beta5 = 5.0-1621 nM), thus demonstrating that conjugation does not impair the exquisite binding profile of this new generation of integrin ligands.