rXXXX American Chemical Society A dx.doi.org/10.1021/ic200132a | Inorg. Chem. XXXX, XXX, 000–000 ARTICLE pubs.acs.org/IC Noncovalent Interaction-Driven Stereoselectivity of Copper(II) Complexes with Cyclodextrin Derivatives of L- and D-Carnosine Giuseppa Ida Grasso, Francesco Bellia, Giuseppe Arena, Graziella Vecchio,* and Enrico Rizzarelli Department of Chemistry, University of Catania, Viale A. Doria 6, 95125 Catania, Italy b S Supporting Information ’ INTRODUCTION The stereoselectivity in the formation of metal complexes with peptide ligands has an important impact in the field of medicinal inorganic chemistry. 1,2 The metal-ion coordination of small peptides is often directly involved in several biochemical pro- cesses. Many papers about the stereoselective formation of transition-metal complexes with oligopeptides have been pub- lished in the last 30 years. 35 The metal binding properties of endogenous compounds greatly influence metallostasis 6 (metal homeostasis), and their study may help in the development of clinical approaches for the treatment of metal-involving pathologies. 7 Carnosine (β-alanyl-L-histidine, LCar), which is found in the muscle and nervous tissues of several animal species, is the most widely and abundantly distributed copper(II)-coordinating en- dogenous dipeptide. 8 Though its physiological role is not completely understood yet, carnosine and other histidine-con- taining dipeptides (homocarnosine and anserine) act in vivo as physiological buffers, wound-healing promoters, ion-chelating agents especially for copper(II) and zinc(II), antioxidants, and free-radical scavengers. 9,10 Its has been proven that carnosine shows antiperoxidative activity on proteins, 11 lipids, 12 and DNA; 13 moreover, it acts as an antioxidant and antiinflammatory agent in lung injury caused by bleomycin administration 14 and ischemia/reperfusion liver injury in rats. 15 Hence, carnosine is widely used for nutraceutical applications. 1619 LCar binding affinity for copper(II) and zinc(II) has been extensively investigated, 20 and it might be crucial in the potential reduction or prevention of several pathologies, such as ALS, Alzheimer’s, and Parkinson’s diseases, 21,22 in which the two metal ions are thought to be involved. 23 Other types of disorders may also be treated with metal complexes of carnosine. For example, it has been shown that the zinc(II) carnosine complex (polaprezinc) is effective for the repair of ulcers and other gut lesions. 24,25 Notwithstanding the beneficial effect of carnosine in several biological processes, its potential therapeutic applications are drastically limited because of hydrolysis by specific dipeptidases, called carnosinases: CN1, the serum-circulating form secreted by brain cells into the cerebrospinal fluid, 2628 and CN2, the nonspecific cytosolic isoform, distributed in several human tissues and in rodent brains. 26,29,30 The chemical modification of L-carnosine is a promising strategy to reduce its enzymatic hydrolysis; 31,32 conjugation of a carbohy- drate moiety may also improve site-specific transport to different tissues, which would enhance the peptide bioavailability. 33,34 Cyclodextrins (CDs) are cyclic chiral oligomers of D-(þ)- glucopyranosyl units linked by R-1,4-glycosidic bonds. These molecules are water-soluble and have the shape of a truncated Received: January 20, 2011 ABSTRACT: L-Carnosine (β-alanyl-L-histidine, LCar) is the most widely and abundantly distributed copper(II)-coordinating endogenous dipeptide. Though its physiological role has not been completely understood yet, many functions have been proposed for this compound. LCar might be crucial in the potential reduction or prevention of several pathologies in which the metal ions are thought to be involved. The potential therapeutic applications of LCar are drastically limited because of hydrolysis by specific dipeptidases (carnosinases). D-Carnosine (DCar), the enantiomer of the naturally occurring dipeptide, shows the same properties as those of LCar, but it is not hydrolyzed by carnosinases. Chemical modification of LCar has been proposed as a promising strategy to reduce its enzymatic hydrolysis; conjugation of a carbohydrate moiety may also improve site-specific transport to different tissues, which would enhance the peptide bioavailability. On this basis, we have functionalized DCar with β-cyclodextrin (CDDCar) and characterized the compound via NMR. The copper(II) binding properties of the new DCar derivative were investigated by spectroscopic techniques (UVvis, circular dichroism, electron paramagnetic resonance) and potentiometric measurements. The results surprisingly revealed a pronounced difference from the analogous LCar derivative (CDLCar), especially concerning the dimeric species. The spectroscopic data show that this stereoselectivity is driven by noncovalent interactions, namely, hydrogen bonds, CHπ interactions, and steric and hydrophobic effects of the cyclodextrin cavity.