Two macrocyclic pentaaza compounds containing pyridine evaluated as novel chelating agents in copper(II) and nickel(II) overload Ana S. Fernandes a , M. Fátima Cabral a , Judite Costa a, ⁎, Matilde Castro a , Rita Delgado b,c , Michael G.B. Drew d , Vitor Félix e a iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal b Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal c Instituto Superior Técnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal d School of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD UK e Departamento de Química, CICECO, and Secção Autónoma de Ciências da Saúde, Universidade de Aveiro, 3810-193 Aveiro, Portugal abstract article info Article history: Received 1 July 2010 Received in revised form 17 November 2010 Accepted 19 November 2010 Available online xxxx Keywords: Macrocyclic compounds Stability constants Chelation therapy Copper(II) complex Nickel(II) complex Two pentaaza macrocycles containing pyridine in the backbone, namely 3,6,9,12,18-pentaazabicyclo[12.3.1] octadeca-1(18),14,16-triene ([15]pyN 5 ), and 3,6,10,13,19-pentaazabicyclo[13.3.1]nonadeca-1(19),15,17- triene ([16]pyN 5 ), were synthesized in good yields. The acid–base behaviour of these compounds was studied by potentiometry at 298.2 K in aqueous solution and ionic strength 0.10 M in KNO 3 . The protonation sequence of [15]pyN 5 was investigated by 1 H NMR titration that also allowed the determination of protonation constants in D 2 O. Binding studies of the two ligands with Ca 2+ , Ni 2+ , Cu 2+ , Zn 2+ , Cd 2+ , and Pb 2+ metal ions were performed under the same experimental conditions. The results showed that all the complexes formed with the 15-membered ligand, particularly those of Cu 2+ and especially Ni 2+ , are thermodynamically more stable than with the larger macrocycle. Cyclic voltammetric data showed that the copper(II) complexes of the two macrocycles exhibited analogous behaviour, with a single quasi-reversible one-electron transfer reduction process assigned to the Cu(II)/Cu(I) couple. The UV–visible-near IR spectroscopic and magnetic moment data of the nickel(II) complexes in solution indicated a tetragonal distorted coordination geometry for the metal centre. X-band EPR spectra of the copper(II) complexes are consistent with distorted square pyramidal geometries. The crystal structure of [Cu([15]pyN 5 )] 2+ determined by X-ray diffraction showed the copper(II) centre coordinated to all five macrocyclic nitrogen donors in a distorted square pyramidal environment. © 2010 Elsevier Inc. All rights reserved. 1. Introduction The therapy for metal overload pathologies usually involves the administration of suitable chelators to selectively remove the metal from the body. Regarding copper(II) and nickel(II) metal ions, there is still a need for safe and efficient chelating agents, as the existing ones have a number of drawbacks such as toxic side effects and controversial efficiency [1]. Copper as an essential element is a component of many metallopro- teins and enzymes and plays a vital role in electron transfer reactions of many cellular processes. However, excessive copper can be very toxic resulting in severe diseases [2]. Certain chelating agents have been shown to bind copper with high affinity. Previous work on copper(II) chelation agents has focused on Wilson's disease, which is an inherited metabolic disease of copper toxicity that is fatal if left untreated [3]. D-Penicillamine has been one of the most commonly used chelating agents for treatment of this disease. When the patient cannot tolerate treatment with D-penicillamine, trien [N,N′-bis(2-aminoethyl)ethane- 1,2-diamine] and ammonium tetrathiomolybdate are considered safer alternatives. Trien is a lesser active agent for copper(II) removal in biological media than D-penicillamine, and although both chelators have similar toxicity, side effects are less frequent and generally milder with D-penicillamine. Ammonium tetrathiomolybdate, acting differently from both D-penicillamine and trien, has been used due to its lower toxic profile, but it is still an experimental drug and its long- term efficacy is unknown [4]. Copper(II) chelation therapy attracts also attention in recent investigations and treatment of neurodegenerative disorders, such as Alzheimer, Parkinson, and Creutzfeldt–Jakob [5]. Furthermore, an excess of copper appears to be an essential co-factor for angiogenesis. Moreover, high levels of copper were found in many human cancers, including prostate, breast, colon, lung, and brain. Consequently, the therapeutic value of copper(II) chelators as anti-angiogenic molecules in the treatment of these cancers has been reported [6]. More recently, mixtures of copper(II) chelators and copper salts were found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells [7]. Journal of Inorganic Biochemistry 105 (2011) 292–301 ⁎ Corresponding author. Fax: +351 217 946 470. E-mail address: jcosta@ff.ul.pt (J. Costa). 0162-0134/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2010.11.014 Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio