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      Zinc Complexes with Nitrogen Donor Ligands as Anticancer Agents

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          Abstract

          The search for anticancer metal-based drugs alternative to platinum derivatives could not exclude zinc derivatives due to the importance of this metal for the correct functioning of the human body. Zinc, the second most abundant trace element in the human body, is one of the most important micro-elements essential for human physiology. Its ubiquity in thousands of proteins and enzymes is related to its chemical features, in particular its lack of redox activity and its ability to support different coordination geometries and to promote fast ligands exchange. Analogously to other trace elements, the impairment of its homeostasis can lead to various diseases and in some cases can be also related to cancer development. However, in addition to its physiological role, zinc can have beneficial therapeutic and preventive effects on infectious diseases and, compared to other metal-based drugs, Zn(II) complexes generally exert lower toxicity and offer few side effects. Zinc derivatives have been proposed as antitumor agents and, among the great number of zinc coordination complexes which have been described so far, this review focuses on the design, synthesis and biological studies of zinc complexes comprising N-donor ligands and that have been reported within the last five years.

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          The role of porphyrin chemistry in tumor imaging and photodynamic therapy.

          In recent years several review articles and books have been published on the use of porphyrin-based compounds in photodynamic therapy (PDT). This critical review is focused on (i) the basic concept of PDT, (ii) advantages of long-wavelength absorbing photosensitizers (PS), (iii) a brief discussion on recent advances in developing PDT agents, and (iv) the various synthetic strategies designed at the Roswell Park Cancer Institute, Buffalo, for developing highly effective long-wavelength PDT agents and their utility in constructing the conjugates with tumor-imaging and therapeutic potential (Theranostics). The clinical status of certain selected PDT agents is also summarized (205 references).
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            Transition metal speciation in the cell: insights from the chemistry of metal ion receptors.

            The essential transition metal ions are avidly accumulated by cells, yet they have two faces: They are put to use as required cofactors, but they also can catalyze cytotoxic reactions. Several families of proteins are emerging that control the activity of intracellular metal ions and help confine them to vital roles. These include integral transmembrane transporters, metalloregulatory sensors, and diffusible cytoplasmic metallochaperone proteins that protect and guide metal ions to targets. It is becoming clear that many of these proteins use atypical coordination chemistry to accomplish their unique goals. The different coordination numbers, types of coordinating residues, and solvent accessibilities of these sites are providing insight into the inorganic chemistry of the cytoplasm.
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              The biological inorganic chemistry of zinc ions☆

              The solution and complexation chemistry of zinc ions is the basis for zinc biology. In living organisms, zinc is redox-inert and has only one valence state: Zn(II). Its coordination environment in proteins is limited by oxygen, nitrogen, and sulfur donors from the side chains of a few amino acids. In an estimated 10% of all human proteins, zinc has a catalytic or structural function and remains bound during the lifetime of the protein. However, in other proteins zinc ions bind reversibly with dissociation and association rates commensurate with the requirements in regulation, transport, transfer, sensing, signalling, and storage. In contrast to the extensive knowledge about zinc proteins, the coordination chemistry of the “mobile” zinc ions in these processes, i.e. when not bound to proteins, is virtually unexplored and the mechanisms of ligand exchange are poorly understood. Knowledge of the biological inorganic chemistry of zinc ions is essential for understanding its cellular biology and for designing complexes that deliver zinc to proteins and chelating agents that remove zinc from proteins, for detecting zinc ion species by qualitative and quantitative analysis, and for proper planning and execution of experiments involving zinc ions and nanoparticles such as zinc oxide (ZnO). In most investigations, reference is made to zinc or Zn2+ without full appreciation of how biological zinc ions are buffered and how the d-block cation Zn2+ differs from s-block cations such as Ca2+ with regard to significantly higher affinity for ligands, preference for the donor atoms of ligands, and coordination dynamics. Zinc needs to be tightly controlled. The interaction with low molecular weight ligands such as water and inorganic and organic anions is highly relevant to its biology but in contrast to its coordination in proteins has not been discussed in the biochemical literature. From the discussion in this article, it is becoming evident that zinc ion speciation is important in zinc biochemistry and for biological recognition as a variety of low molecular weight zinc complexes have already been implicated in biological processes, e.g. with ATP, glutathione, citrate, ethylenediaminedisuccinic acid, nicotianamine, or bacillithiol.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                09 December 2020
                December 2020
                : 25
                : 24
                : 5814
                Affiliations
                [1 ]ICMATE-C.N.R., Corso Stati Uniti 4, 35127 Padova, Italy
                [2 ]Chemistry Division, School of Science and Technology, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy; carlo.santini@ 123456unicam.it
                [3 ]Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy; fabio.delbello@ 123456unicam.it
                Author notes
                Author information
                https://orcid.org/0000-0003-0435-6576
                https://orcid.org/0000-0001-5020-1730
                https://orcid.org/0000-0001-6538-6029
                https://orcid.org/0000-0002-3942-1713
                Article
                molecules-25-05814
                10.3390/molecules25245814
                7763991
                33317158
                a393b04f-1127-4aa9-b65b-2c1ae341c5ae
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 07 November 2020
                : 07 December 2020
                Categories
                Review

                zinc(ii),zinc(ii) complexes,n-donor ligands,medicinal chemistry,antitumor agents

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