7680 | New J. Chem., 2018, 42, 7680--7690 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 Cite this: New J. Chem., 2018, 42, 7680 New curcumin-derived ligands and their affinity towards Ga 3+ , Fe 3+ and Cu 2+ : spectroscopic studies on complex formation and stability in solution† Luca Rigamonti, a Giulia Orteca, a Mattia Asti, b Valentina Basile, c Carol Imbriano, c Monica Saladini a and Erika Ferrari * a The metal complexing ability in solution of four substituted curcumin (CUR)-derived ligands K3T, originated by the insertion of the –CH 2 CH 2 COOtBu branch on the central atom of the diketonic moiety of CUR and related derivatives with variable meta and para substituents (OH, OMe, H, OCOCH 3 ) on the peripheral aromatic rings, is examined. These molecules can act as new chelators with biological proper- ties comparable to those of CUR but with improved stability. In fact, curcuminoids represent new perspectives for the development of novel therapeutic agents for several diseases including Alzheimer’s disease. CUR showed neuroprotective properties, and a probable mechanism of its action is related to the complexation ability towards endogenous metal ions Fe 3+ and Cu 2+ . K3T derivatives retain the solvent-dependent diketo–ketoenol tautomerism, with the prevalence of the diketonic form in aqueous solution. They show enhanced stability in simulated physiological conditions (phosphate buffered solution at pH = 7.4) compared to CUR, together with similar or even higher anti-proliferative activity against human colon carcinoma cells HCT116. The addition of the metal ion causes dissociation of the enolic proton creating chelate complexes and shift of the tautomeric equilibrium toward the keto–enol species. The formation of metal complexes was followed and confirmed by both NMR (using Ga 3+ as a diamagnetic probe for Fe 3+ ) and UV-visible spectroscopy. All the ligands showed high affinity for Fe 3+ and Ga 3+ , forming M : L 1 : 2 species. In view of therapeutic applications, notable is the good affinity of K3T31, i.e. the ligand bearing only OH groups in para positions of the aromatic rings, for Cu 2+ , and the ability of the Cu : K3T31 1 : 1 complex to bind to DNA. Introduction In ancient times, pharmaceutical agents were generally derived from medicinal plants, and among them Curcuma longa L. is outstanding for its precious extract that has been used by traditional Ayurveda medicine for thousands of years. 1,2 The dried rhizome of Curcuma longa L. has been widely used as an aromatic stomachic, carminative, anthelmintic, laxative, as well as for liver ailments, in food dyes, and as a preservative. 1 Curcumin (CUR), 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione, is the primary bioactive compound isolated from this spice. In the past decade, a large number of reports have been published on the beneficial effects of CUR, 2,3 particularly its therapeutic activity against various tumours, inhibiting the initiation, progression and survival of tumor cells. 4–6 More interestingly, a valuable feature of plant-derived poly- phenolic compounds such as CUR is their ability to behave as antioxidants and as free-radical trapping agents, assumed to be an important cytoprotective attribute. 2–6 LoPachin et al. 7 high- lighted how the b-diketonic moiety within the heptadiene chain of CUR plays a major role in reducing oxidative stress, particularly by acting as a bidentate chelator of metal ions like Fe 3+ and Cu 2+ , 8 which can take place in the Fenton reaction. Although the molecular a Dipartimento di Scienze Chimiche e Geologiche, Universita` degli Studi di Modena e Reggio Emilia, via G. Campi 103, 41125 Modena, Italy. E-mail: erika.ferrari@unimore.it; Tel: +39 0592058631 b Nuclear Medicine Unit – Advanced Technology Department, AUSL – IRCCS Reggio Emilia, viale Amendola 2, 42122 Reggio Emilia, Italy c Dipartimento di Scienze della Vita, Universita ` degli Studi di Modena e Reggio Emilia, via G. Campi 103, 41125 Modena, Italy † Electronic supplementary information (ESI) available: pH-Metric spectrophoto- metric titration of K3T31, K3T33 and K3T24 in aqueous medium ([NaNO 3 ]= 0.1 mol L 1 , 298 K) in the 250–600 nm spectral range, pH starting from 5.5 to 11.0 (Fig. S1); 1 H NMR spectrum of K3T21 in CD 3 OD at 298 K in the 6–8 and 1–5 ppm ranges (Fig. S2); 1 H and 13 C NMR chemical shifts of the Ga 3+ : K3T21 1 : 1 complex in CD 3 OD at 298 K (Table S1); pH-metric spectrophotometric titration of M n+ : K3T 1 : 1 systems in aqueous medium ([NaNO 3 ] = 0.1 mol L 1 , 298 K) in the 250–600 nm spectral range, pH starting from around 5 to 11 (Fig. S3–S5). See DOI: 10.1039/c8nj00535d Received 30th January 2018, Accepted 2nd March 2018 DOI: 10.1039/c8nj00535d rsc.li/njc NJC PAPER Published on 05 March 2018. Downloaded by Universita Degli Studi di Modena on 15/05/2018 07:49:17. View Article Online View Journal | View Issue