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      Preface to “A Commemorative Issue in Honour of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA”

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      International Journal of Molecular Sciences
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          Abstract

          This Special Issue of the International Journal of Molecular Science comprises a comprehensive study on "Metal Complex Interactions with Nucleic Acids and/or DNA". This Special Issue has been inspired by the important contribution of Prof. Nick Hadjiliadis in the field of palladium or/and platinum/nucleic acid interactions. It covers a selection of recent research and review articles in the field of metal complex interactions with nucleic acids and/or DNA. Metal complexes have long been recognized as critically important components of nucleic acid chemistry, both in the regulation of gene expression and as promising therapeutic agents. The ability to recognize and understand how metal complexes interact with DNA at the molecular level has become an active research area at the interface between biological inorganic chemistry, molecular biology, and medicine. Arguably the most prominent drug which contains a metal is cisplatin, the most widely used anti-cancer drug. The success of cisplatin in chemotherapy and the clarification of its mechanism of action through its interaction with DNA has motivated a large number of studies on metal complex interactions with nucleic acids or/and DNA. Thus, the reader of this Special Issue will gain an appreciation of the real role of the interactions of metal complexes with nucleic acids or/and DNA in modern medicine. This Special Issue on "Metal complex Interactions with Nucleic Acids and/or DNA" provides an overview of this increasingly diverse field, presenting recent developments and the latest research with particular emphasis on metal-based drugs and metal ion toxicity. Inorganic biochemistry or bioinorganic chemistry is a multidiscipline field which involves inorganic chemistry, biochemistry, spectroscopy, material science, biology, and medicine. The introduction of metal ions or metal ion binding components into a biological system for the treatment of diseases is one of the main subdivisions in the field of inorganic biochemistry. Nowadays, at the forefront of the field is the development of new metallodrugs for diagnostics (radiopharmaceuticals drugs), medicines (anticancer, antimicrobial/antiparasitic, therapeutic radiopharmaceuticals, photochemotherapeutic metallodrugs, antiarthritic, antidiabetes, antiviral, metallodrugs addressing deficiencies syndromes), and tools for chemical biology, biocatalysis, and bioelectronics, as well as the characterization of metalloproteins, enzymes, and their model complexes. Recently, biomaterials have been applied in many cases such as cardiovascular medical devices, orthopedic and dental applications, ophthalmologic applications, bioelectrodes and biosensors, burn dressings and skin substitutes, sutures, and drug delivery systems. For the coming years, the well-defined bioavailability, absorption, distribution, metabolism, and excretion of metal-based drugs will be the main target of new metallodrugs. The use of nanoparticles, micelle emulsions, and liposomal formulations can open new opportunities for improved delivery, cell uptake, and targeting. Emeritus Professor Nick Hadjiliadis is one of the pioneers in the field of bioinorganic chemistry. He graduated from the University of Athens, and subsequently earned a Masters in Science from the University of Montreal and a Doctor of Chemistry, PhD from the University of Montreal in 1975. He served as a Professor of Inorganic and General Chemistry at the Department of Chemistry of the University of Ioannina, Greece, since 1980. He worked on the interaction of metal ions with nucleobases and nucleosides, as well as with DNA and RNA. This pioneering work led to the first conclusions elucidating the mechanism of the antitumoral action of cisplatin. His research interests also included: (i) the synthesis, characterization, and study of the antitumor properties of new metal complexes (e.g., Pt, Pd, Sn, Sb, etc.); (ii) the study of metalloenzyme models and the clarification of their mechanism of action. His research on thiamine enzymes in the presence of divalent metal ions, for which he proposed a mechanism, was also a pioneering work in the field of enzyme/metal ion interactions. He also studied (iii) the mechanism of action of superoxide dismutase, Cu(II), and Zn(II); (iv) peptide interactions with metal ions, as models of enzymes or other biological systems; (v) the involvement of metal ions such as Ni(II) and Cu(II) in carcinogenesis; (vi) the biocatalysis of new materials; (vii) the mechanism of action of anti-thyroid drugs; (viii) organometallic chemistry, etc. He has numerous publications (up to 260), which have been cited more than 7000 times with an h-index of 44. He has been invited to 70 international conferences (as a Lead Speaker). He has coordinated many research and teaching programs. Important international conferences dedicated to the field of inorganic biochemistry—such as 5-ISABC, HALCHEM-III, 12-EURASIA, etc.—have been organized and chaired by him. Furthermore, he mentored many scientists, initiating their careers as academicians worldwide. Special attention should be paid to his contribution to the foundation and operation of the Interdisciplinary Program of Postgraduate Studies in Bioinorganic Chemistry, which he led for a decade. His contribution to the field of Inorganic-Bioinorganic Chemistry is undoubtedly superior in quality and unique for a Greek scientist. Overall, he contributed to the progress of inorganic chemistry not only at the University of Ioannina, Greece, but in the whole nation. Recognizing this contribution of Emeritus Professor Nick Hadjiliadis to the field of inorganic biochemistry and especially to the field of palladium or/and platinum/nucleic acid interactions, it is our honour to dedicate the prologue of this commemorative issue of the International Journal of Molecular Sciences to him. This Special Issue is composed of 14 articles, which are briefly reviewed below. Yu-Wen Chen et al. showed that the i-motif DNA sequence may transition to a base-extruded duplex structure with a GGCC tetranucleotide tract when it is bound to the (CoII)-mediated dimer of chromomycin A3 [1]. G. Momekov et al. investigated two paramagnetic palladium(III) complexes of hematoporphyrin IX for their ability to process DNA adducts as well as for their antineoplastic and apoptogenic activities [2]. E. Makkonen et al. reported a combined quantum mechanics/molecular mechanics molecular dynamics and time-dependent density functional study of silver-mediated deoxyribonucleic acid nanostructures [3]. S. Liu et al. investigated the interactions between ruthenium(II) complexes and 15-mer single- and double-stranded oligodeoxynucleotides and they tested the thermodynamic base and sequence selectivity [4]. G.K. Latsis et al. investigated two polyorganotic acetate complexes against DNA with possible implementation towards breast cancer cells [5]. S. Savino et al. tested the ability of platinum prodrugs of kiteplatin with a-lipoic acid in the axial position to target in mitochondria [6]. Q.Y. Yang et al. tested the molecular mechanism of two transition metal complexes with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol against tumor cells [7]. M. Hande et al. described the synthesis and hybridization properties of short oligonucleotides incorporating cyclopalladated benzylamine “warheads” at their 5′-termini [8]. M.F. AlAjmi et al. evaluated the benzimidazole-derived biocompatible copper(II) and zinc(II) complexes as anticancer chemotherapeutics [9]. T. Qin et al. examined the binding of zinc cationic porphyrin towards B-DNA and Z-DNA [10] A.B. Olejniczak et al. presented an overview of the methods for incorporating metal centers into nucleic acids based on metal–boron cluster complexes (metallacarboranes) as the metal carriers [11]. Y.H. Lai et al. reviewed the mechanisms by which the regulation of copper homeostasis modulates the chemosensitivity of tumors to platinum drugs [12]. V. Murray et al. reviewed the abilities of bleomycin to interact with DNA [13]. N.C. Sabharwal et al. investigated the interactions between spermine-derivitized tentacle 2 porphyrins and the human telomeric DNA G quadruplex [14].

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          Most cited references14

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          The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

          The cancer chemotherapeutic drug, bleomycin, is clinically used to treat several neoplasms including testicular and ovarian cancers. Bleomycin is a metallo-glycopeptide antibiotic that requires a transition metal ion, usually Fe(II), for activity. In this review, the properties of bleomycin are examined, especially the interaction of bleomycin with DNA. A Fe(II)-bleomycin complex is capable of DNA cleavage and this process is thought to be the major determinant for the cytotoxicity of bleomycin. The DNA sequence specificity of bleomycin cleavage is found to at 5′-GT* and 5′-GC* dinucleotides (where * indicates the cleaved nucleotide). Using next-generation DNA sequencing, over 200 million double-strand breaks were analysed, and an expanded bleomycin sequence specificity was found to be 5′-RTGT*AY (where R is G or A and Y is T or C) in cellular DNA and 5′-TGT*AT in purified DNA. The different environment of cellular DNA compared to purified DNA was proposed to be responsible for the difference. A number of bleomycin analogues have been examined and their interaction with DNA is also discussed. In particular, the production of bleomycin analogues via genetic manipulation of the modular non-ribosomal peptide synthetases and polyketide synthases in the bleomycin gene cluster is reviewed. The prospects for the synthesis of bleomycin analogues with increased effectiveness as cancer chemotherapeutic agents is also explored.
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            Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis

            Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting—carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively—cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. hCtr1 expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates hCtr1. Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy.
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              Design, Synthesis, and Biological Evaluation of Benzimidazole-Derived Biocompatible Copper(II) and Zinc(II) Complexes as Anticancer Chemotherapeutics

              Herein, we have synthesized and characterized a new benzimidazole-derived “BnI” ligand and its copper(II) complex, [Cu(BnI)2], 1, and zinc(II) complex, [Zn(BnI)2], 2, using elemental analysis and various spectroscopic techniques. Interaction of complexes 1 and 2 with the biomolecules viz. HSA (human serum albumin) and DNA were studied using absorption titration, fluorescence techniques, and in silico molecular docking studies. The results exhibited the significant binding propensity of both complexes 1 and 2, but complex 1 showed more avid binding to HSA and DNA. Also, the nuclease activity of 1 and 2 was analyzed for pBR322 DNA, and the results obtained confirmed the potential of the complexes to cleave DNA. Moreover, the mechanistic pathway was studied in the presence of various radical scavengers, which revealed that ROS (reactive oxygen species) are responsible for the nuclease activity in complex 1, whereas in complex 2, the possibility of hydrolytic cleavage also exists. Furthermore, the cytotoxicity of the ligand and complexes 1 and 2 were studied on a panel of five different human cancer cells, namely: HepG2, SK-MEL-1, HT018, HeLa, and MDA-MB 231, and compared with the standard drug, cisplatin. The results are quite promising against MDA-MB 231 (breast cancer cell line of 1), with an IC50 value that is nearly the same as the standard drug. Apoptosis was induced by complex 1 on MDA-MB 231 cells predominantly as studied by flow cytometry (FACS). The adhesion and migration of cancer cells were also examined upon treatment of complexes 1 and 2. Furthermore, the in vivo chronic toxicity profile of complexes 1 and 2 was also studied on all of the major organs of the mice, and found them to be less toxic. Thus, the results warrant further investigations of complex 1.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                30 November 2018
                December 2018
                : 19
                : 12
                : 3815
                Affiliations
                Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece; cbanti@ 123456cc.uoi.gr
                Author notes
                [* ]Correspondence: shadjika@ 123456uoi.gr ; Tel.: +30-2651-008374
                Author information
                https://orcid.org/0000-0001-6727-2711
                https://orcid.org/0000-0001-9556-6266
                Article
                ijms-19-03815
                10.3390/ijms19123815
                6320841
                30513581
                04dd6c19-477f-4fb8-b28a-ba6276c4af83
                © 2018 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
                : 27 November 2018
                : 30 November 2018
                Categories
                Editorial

                Molecular biology
                Molecular biology

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