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Recent Advances in Metal Based Drugs

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioinorganic Chemistry".

Deadline for manuscript submissions: closed (30 April 2017) | Viewed by 77964

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Special Issue Editors

Prof. Dr. Nick Hadjiliadis

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Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
Interests: metal ions in biological systems; (bioinorganic chemistry) study by physiochemical and spectroscopic methods (IR-Raman, UV-Vis, multinuclear and multidimensional NMR, Mössbauer etc and X-ray crystallography) of metalloenzyme models, like thiamine, SOD and others; metal based antitumor drugs, including Pt(II), Ru(II), Sn(IV) etc.; metal interaction with DNA and RNA constituents aminoacids and oligopeptides as enzyme models; metal induced carcinogennesis; thioamide charge transfer complexes of I2 and mechanism of action of antithyroid drugs; biocatalysis

Prof. Dr. Sotiris Hadjikakou

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Department of Chemistry, University of Ioannina, 451 10 Ioannina, Greece
Interests: crystal structure; structure determination; material characterization; structural chemistry; biological inorganic chemistry, antimicrobial compounds; antiproliferative compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of IJMS, entitled “Recent Advances in Metal Based Drugs”, will cover a selection of recent research and review articles in the field of metal based drugs. The use of metals in medicine goes back to antiquity, with various elements, such as arsenic, gold, and iron, being used to treat different ailments. Nowadays, the medicinal uses and applications of metals and metal complexes are of increasing clinical and commercial importance. A reasonable estimate of commercial importance is approaching US $5 billion annually for the whole field.

The ability to recognize, to understand at the molecular level, and to treat diseases caused by inadequate metal-ion function constitutes an important aspect of medicinal bioinorganic chemistry. Diseases such as anemia (iron), asthma (gold and magnesium), bipolar disorder (lithium), diabetes (vanadium), rheumatoid arthritis (gold), stroke (magnesium), tropical diseases (antimony and rhodium), and ulcers (bismuth) can be treated by metal-based drugs. Arguably, the most prominent drug that contains a metal is cisplatin, the most widely used anti-cancer drug. The success of cisplatin in chemotherapy has motivated a large number of studies into the potential for other platinum and other metal (like palladium, silver, tin, antimony, etc.) complexes as anti-tumor drugs.

From the foregoing, the reader of this Special Issue will gain an appreciation of the very real roles metal-based drugs play. In modern medicine, the considerable effort being devoted to the development of novel complexes with greater efficacies and reduced toxic side effects (an inevitable consequence of all chemotherapy) will be appreciated.

Prof. Dr. Sotiris Hadjikakou
Prof. Dr. Nick Hadjiliadis
Guest Editors

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Keywords

Metal Based Drugs
Metallotharapeutic Drugs
Metals in Medicine
Platinum Complexes as Therapeutic Agents
Non-platinum Anticancer Agents
Antibacterial Agents
Radioimmunoimaging and Radioimmunotherapy
Metal Based Diagnostic Agents

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2350 KiB

Open AccessArticle

Antiplatelet Activity of a Newly Synthesized Novel Ruthenium (II): A Potential Role for Akt/JNK Signaling

by Themmila Khamrang, Kuo-Chen Hung, Chih-Hsuan Hsia, Cheng-Ying Hsieh, Marappan Velusamy, Thanasekaran Jayakumar and Joen-Rong Sheu

Int. J. Mol. Sci. 2017, 18(5), 916; https://doi.org/10.3390/ijms18050916 - 27 Apr 2017

Cited by 11 | Viewed by 4368

Abstract

In oncotherapy, ruthenium complexes are considered as potential alternatives for platinum compounds, and have been proved as promising anticancer drugs with high efficacy and lesser side effects. Platelet activation plays a major role in cancer metastasis and progression. Hence, this study explored the effect of a newly synthesized ruthenium complex, [Ru(η⁶-cymene)(L)Cl]BF₄(TQ5), where L = 4-phenyl-2-pyridin-2-yl-quinazoline), on human platelet activation. TQ5 (3–5 µM) inhibited concentration-dependent collagen-induced platelet aggregation in washed human platelets. However, this compound only inhibited platelet aggregation at a maximum concentration of 500 and 100 µM against thrombin and 9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin (U46619)-induced stimulation, respectively. TQ5 inhibited collagen-induced ATP release and calcium mobilization ([Ca²⁺]_i), without inducing cell cytotoxicity. In addition, neither SQ22536, an adenylate cyclase inhibitor, nor 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor, significantly reversed the TQ5-mediated inhibition of platelet aggregation. TQ5 inhibited the collagen-induced phosphorylation of protein kinase B (Akt) and c-Jun N-terminal kinase (JNK), but did not effectively inhibit extracellular signal-regulated kinase 1/2 (ERK1/2) and p38-mitogen-activated protein kinase (p38-MAPK) in human platelets. Additionally, TQ5 significantly prolonged the closure time in whole blood and increased the occlusion time of thrombotic platelet plug formation in mice. This study demonstrates, for the first time, that a newly synthesized ruthenium complex, TQ5, exhibits potent antiplatelet activity by hindering ATP release and [Ca²⁺]_i, and by decreasing the activation of Akt/JNK signals. Together, these results suggest that TQ5 could be developed as a therapeutic agent that helps prevent or treat thromboembolic disorders, since it is found to be potently more effective than a well-established antithrombotic aspirin. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Open AccessArticle

Affinity of ^nat/68Ga-Labelled Curcumin and Curcuminoid Complexes for β-Amyloid Plaques: Towards the Development of New Metal-Curcumin Based Radiotracers

by Sara Rubagotti, Stefania Croci, Erika Ferrari, Michele Iori, Pier C. Capponi, Luca Lorenzini, Laura Calzà, Annibale Versari and Mattia Asti

Int. J. Mol. Sci. 2016, 17(9), 1480; https://doi.org/10.3390/ijms17091480 - 06 Sep 2016

Cited by 13 | Viewed by 5805

Abstract

Curcumin derivatives labelled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer’s disease. Nevertheless, no study by exploiting the labelling with gallium-68 has been performed so far, in spite of its suitable properties (positron emitter, generator produced radionuclide). Herein, an evaluation of the affinity for synthetic β-amyloid fibrils and for amyloid plaques of three ^nat/68Ga-labelled curcumin analogues, namely curcumin curcumin (CUR), bis-dehydroxy-curcumin (bDHC) and diacetyl-curcumin (DAC), was performed. Affinity and specificity were tested in vitro on amyloid synthetic fibrils by using gallium-68 labelled compounds. Post-mortem brain cryosections from Tg2576 mice were used for the ex vivo visualization of amyloid plaques. The affinity of ⁶⁸Ga(CUR)₂⁺, ⁶⁸Ga(DAC)₂⁺, and ⁶⁸Ga(bDHC)₂⁺ for synthetic β-amyloid fibrils was moderate and their uptake could be observed in vitro. On the other hand, amyloid plaques could not be visualized on brain sections of Tg2576 mice after injection, probably due to the low stability of the complexes in vivo and of a hampered passage through the blood–brain barrier. Like curcumin, all ^nat/68Ga-curcuminoid complexes maintain a high affinity for β-amyloid plaques. However, structural modifications are still needed to improve their applicability as radiotracers in vivo. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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The Iron Chelator, Dp44mT, Effectively Inhibits Human Oral Squamous Cell Carcinoma Cell Growth in Vitro and in Vivo

by Jehn-Chuan Lee, Kun-Chun Chiang, Tsui-Hsia Feng, Yu-Jen Chen, Sung-Ting Chuang, Ke-Hung Tsui, Li-Chuan Chung and Horng-Heng Juang

Int. J. Mol. Sci. 2016, 17(9), 1435; https://doi.org/10.3390/ijms17091435 - 31 Aug 2016

Cited by 41 | Viewed by 5933

Abstract

Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Pharmacological Activities of Ruthenium Complexes Related to Their NO Scavenging Properties

by Anna Castellarin, Sonia Zorzet, Alberta Bergamo and Gianni Sava

Int. J. Mol. Sci. 2016, 17(8), 1254; https://doi.org/10.3390/ijms17081254 - 02 Aug 2016

Cited by 10 | Viewed by 4842

Abstract

Angiogenesis is considered responsible for the growth of primary tumours and of their metastases. With the present study, the effects of three ruthenium compounds, potassiumchlorido (ethylendiamminotetraacetate)rutenate(III) (RuEDTA), sodium (bis-indazole)tetrachloro-ruthenate(III), Na[trans-RuCl₄Ind₂] (KP1339) and trans-imidazoledimethylsulphoxidetetrachloro-ruthenate (NAMI-A), are studied in vitro in models mimicking the angiogenic process. The ruthenium compounds reduced the production and the release of nitrosyls from either healthy macrophages and immortalized EA.hy926 endothelial cells. The effects of NAMI-A are qualitatively similar and sometimes quantitatively superior to those of RuEDTA and KP1339. NAMI-A reduces the production and release of nitric oxide (NO) by the EA.hy926 endothelial cells and correspondingly inhibits their invasive ability; it also strongly inhibits the angiogenesis in matrigel sponges implanted subcutaneously in healthy mice. Taken together, these data support the anti-angiogenic activity of the tested ruthenium compounds and they contribute to explain the selective activity of NAMI-A against solid tumour metastases, the tumour compartment on which angiogenesis is strongly involved. This anti-angiogenic effect may also contribute to the inhibition of the release of metastatic cells from the primary tumour. Investigations on the anti-angiogenic effects of NAMI-A at this level will increase knowledge of its pharmacological properties and it will give a further impulse to the development of this class of innovative metal-based drugs. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Assessment of Dextran Antigenicity of Intravenous Iron Preparations with Enzyme-Linked Immunosorbent Assay (ELISA)

by Susann Neiser, Taija S. Koskenkorva, Katrin Schwarz, Maria Wilhelm and Susanna Burckhardt

Int. J. Mol. Sci. 2016, 17(7), 1185; https://doi.org/10.3390/ijms17071185 - 21 Jul 2016

Cited by 21 | Viewed by 7962

Abstract

Intravenous iron preparations are typically classified as non-dextran-based or dextran/dextran-based complexes. The carbohydrate shell for each of these preparations is unique and is key in determining the various physicochemical properties, the metabolic pathway, and the immunogenicity of the iron-carbohydrate complex. As intravenous dextran can cause severe, antibody-mediated dextran-induced anaphylactic reactions (DIAR), the purpose of this study was to explore the potential of various intravenous iron preparations, non-dextran-based or dextran/dextran-based, to induce these reactions. An IgG-isotype mouse monoclonal anti-dextran antibody (5E7H3) and an enzyme-linked immunosorbent assay (ELISA) were developed to investigate the dextran antigenicity of low molecular weight iron dextran, ferumoxytol, iron isomaltoside 1000, ferric gluconate, iron sucrose and ferric carboxymaltose, as well as isomaltoside 1000, the isolated carbohydrate component of iron isomaltoside 1000. Low molecular weight iron dextran, as well as dextran-based ferumoxytol and iron isomaltoside 1000, reacted with 5E7H3, whereas ferric carboxymaltose, iron sucrose, sodium ferric gluconate, and isolated isomaltoside 1000 did not. Consistent results were obtained with reverse single radial immunodiffusion assay. The results strongly support the hypothesis that, while the carbohydrate alone (isomaltoside 1000) does not form immune complexes with anti-dextran antibodies, iron isomaltoside 1000 complex reacts with anti-dextran antibodies by forming multivalent immune complexes. Moreover, non-dextran based preparations, such as iron sucrose and ferric carboxymaltose, do not react with anti-dextran antibodies. This assay allows to assess the theoretical possibility of a substance to induce antibody-mediated DIARs. Nevertheless, as this is only one possible mechanism that may cause a hypersensitivity reaction, a broader set of assays will be required to get an understanding of the mechanisms that may lead to intravenous iron-induced hypersensitivity reactions. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Open AccessArticle

Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism

by Haseeb Zubair, Shafquat Azim, Husain Yar Khan, Mohammad Fahad Ullah, Daocheng Wu, Ajay Pratap Singh, Sheikh Mumtaz Hadi and Aamir Ahmad

Int. J. Mol. Sci. 2016, 17(6), 973; https://doi.org/10.3390/ijms17060973 - 20 Jun 2016

Cited by 17 | Viewed by 6815

Abstract

There is compelling evidence that serum, tissue and intracellular levels of copper are elevated in all types of cancer. Copper has been suggested as an important co-factor for angiogenesis. It is also a major metal ion present inside the nucleus, bound to DNA bases, particularly guanine. We have earlier proposed that the interaction of phenolic-antioxidants with intracellular copper leads to the generation of reactive oxygen species (ROS) that ultimately serve as DNA cleaving agents. To further validate our hypothesis we show here that the antioxidant gossypol and its semi-synthetic derivative apogossypolone induce copper-mediated apoptosis in breast MDA-MB-231, prostate PC3 and pancreatic BxPC-3 cancer cells, through the generation of ROS. MCF10A breast epithelial cells refractory to the cytotoxic property of these compounds become sensitized to treatment against gossypol, as well as apogossypolone, when pre-incubated with copper. Our present results confirm our earlier findings and strengthen our hypothesis that plant-derived antioxidants mobilize intracellular copper instigating ROS-mediated cellular DNA breakage. As cancer cells exist under significant oxidative stress, this increase in ROS-stress to cytotoxic levels could be a successful anticancer approach. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Novel Zinc(II) Complexes [Zn(atc-Et)₂] and [Zn(atc-Ph)₂]: In Vitro and in Vivo Antiproliferative Studies

by Erica De O. Lopes, Carolina G. de Oliveira, Patricia B. da Silva, Carlos E. Eismann, Carlos A. Suárez, Amauri A. Menegário, Clarice Q. F. Leite, Victor M. Deflon and Fernando R. Pavan

Int. J. Mol. Sci. 2016, 17(5), 781; https://doi.org/10.3390/ijms17050781 - 21 May 2016

Cited by 22 | Viewed by 5804

Abstract

Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn^II) thiosemicarbazone complexes [Zn(atc-Et)₂] (1) and [Zn(atc-Ph)₂] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Ruthenium Complexes Induce HepG2 Human Hepatocellular Carcinoma Cell Apoptosis and Inhibit Cell Migration and Invasion through Regulation of the Nrf2 Pathway

by Yiyu Lu, Ting Shen, Hua Yang and Weiguang Gu

Int. J. Mol. Sci. 2016, 17(5), 775; https://doi.org/10.3390/ijms17050775 - 19 May 2016

Cited by 27 | Viewed by 6510

Abstract

Ruthenium (Ru) complexes are currently the focus of substantial interest because of their potential application as chemotherapeutic agents with broad anticancer activities. This study investigated the in vitro and in vivo anticancer activities and mechanisms of two Ru complexes—2,3,7,8,12,13,17,18-Octaethyl-21H,23H-porphine Ru(II) carbonyl (Ru1) and 5,10,15,20-Tetraphenyl-21H,23H-porphine Ru(II) carbonyl (Ru2)—against human hepatocellular carcinoma (HCC) cells. These Ru complexes effectively inhibited the cellular growth of three human hepatocellular carcinoma (HCC) cells, with IC₅₀ values ranging from 2.7–7.3 μM. In contrast, the complexes exhibited lower toxicity towards L02 human liver normal cells with IC₅₀ values of 20.4 and 24.8 μM, respectively. Moreover, Ru2 significantly inhibited HepG2 cell migration and invasion, and these effects were dose-dependent. The mechanistic studies demonstrated that Ru2 induced HCC cell apoptosis, as evidenced by DNA fragmentation and nuclear condensation, which was predominately triggered via caspase family member activation. Furthermore, HCC cell treatment significantly decreased the expression levels of Nrf2 and its downstream effectors, NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1). Ru2 also exhibited potent in vivo anticancer efficacy in a tumor-bearing nude mouse model, as demonstrated by a time- and dose-dependent inhibition on tumor growth. The results demonstrate the therapeutic potential of Ru complexes against HCC via Nrf2 pathway regulation. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Metal Complexes of New Bioactive Pyrazolone Phenylhydrazones; Crystal Structure of 4-Acetyl-3-methyl-1-phenyl-2-pyrazoline-5-one phenylhydrazone Ampp-Ph

by Omoruyi G. Idemudia, Alexander P. Sadimenko and Eric C. Hosten

Int. J. Mol. Sci. 2016, 17(5), 687; https://doi.org/10.3390/ijms17050687 - 18 May 2016

Cited by 21 | Viewed by 7257

Abstract

The condensation reaction of phenylhydrazine and dinitrophenylhydrazine with 4-acetyl and 4-benzoyl pyrazolone precipitated air-stable acetyldinitrophenylhydrazone Ampp-Dh, benzoylphenylhydrazone Bmpp-Ph and benzoyldinitrophenylhydrazone Bmpp-Dh in their keto imine form; a study inspired by the burning interest for the development of new bioactive materials with novel properties that may become alternative therapeutic agents. Elemental analysis, FTIR, ¹H, and ¹³C NMR, and mass spectroscopy have been used to justify their proposed chemical structures, which were in agreement with the single crystal structure of Bmpp-Dh earlier reported according to X-ray crystallography. The single crystal structure of 4-acetyl-3-methyl-1-phenyl--pyrazoline-5-one phenylhydrazone Ampp-Ph, which crystallizes in a triclinic crystal system with a P-1 (No. 2) space group is presented. Octahedral Mn(II), Ni(II), Co(II), and Cu(II) complexes of these respective ligands with two molecules each of the bidentate Schiff base, coordinating to the metal ion through the azomethine nitrogen C=N and the keto oxygen C=O, which were afforded by the reaction of aqueous solutions of the corresponding metal salts with the ligands are also reported. Their identity and proposed structures were according to elemental analysis, FTIR spectroscopy, UV-VIS spectrophotometry (electronic spectra) and Bohr magnetic moments, as well as thermogravimetric analysis (TGA) results. A look at the antibacterial and antioxidant activities of synthesized compounds using the methods of the disc diffusion against some selected bacterial isolates and 1,1-diphenyl-2-picryl-hydrazil (DPPH) respectively, showed biological activities in relation to employed standard medicinal drugs. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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In Vitro Activity of Copper(II) Complexes, Loaded or Unloaded into a Nanostructured Lipid System, against Mycobacterium tuberculosis

by Patricia B. da Silva, Paula C. de Souza, Giovana Maria Fioramonti Calixto, Erica De O. Lopes, Regina C. G. Frem, Adelino V. G. Netto, Antonio E. Mauro, Fernando R. Pavan and Marlus Chorilli

Int. J. Mol. Sci. 2016, 17(5), 745; https://doi.org/10.3390/ijms17050745 - 17 May 2016

Cited by 27 | Viewed by 5834

Abstract

Tuberculosis (TB) is an infectious disease caused mainly by the bacillus Mycobacterium tuberculosis (Mtb), presenting 9.5 million new cases and 1.5 million deaths in 2014. The aim of this study was to evaluate a nanostructured lipid system (NLS) composed of 10% phase oil (cholesterol), 10% surfactant (soy phosphatidylcholine, sodium oleate), and Eumulgin^® HRE 40 ([castor oil polyoxyl-40-hydrogenated] in a proportion of 3:6:8), and an 80% aqueous phase (phosphate buffer pH = 7.4) as a tactic to enhance the in vitro anti-Mtb activity of the copper(II) complexes [CuCl₂(INH)₂]·H₂O (1), [Cu(NCS)₂(INH)₂]·5H₂O (2) and [Cu(NCO)₂(INH)₂]·4H₂O (3). The Cu(II) complex-loaded NLS displayed sizes ranging from 169.5 ± 0.7095 to 211.1 ± 0.8963 nm, polydispersity index (PDI) varying from 0.135 ± 0.0130 to 0.236 ± 0.00100, and zeta potential ranging from −0.00690 ± 0.0896 to −8.43 ± 1.63 mV. Rheological analysis showed that the formulations behave as non-Newtonian fluids of the pseudoplastic and viscoelastic type. Antimycobacterial activities of the free complexes and NLS-loaded complexes against Mtb H₃₇Rv ATCC 27294 were evaluated by the REMA methodology, and the selectivity index (SI) was calculated using the cytotoxicity index (IC₅₀) against Vero (ATCC^® CCL-81), J774A.1 (ATCC^® TIB-67), and MRC-5 (ATCC^® CCL-171) cell lines. The data suggest that the incorporation of the complexes into NLS improved the inhibitory action against Mtb by 52-, 27-, and 4.7-fold and the SI values by 173-, 43-, and 7-fold for the compounds 1, 2 and 3, respectively. The incorporation of the complexes 1, 2 and 3 into the NLS also resulted in a significant decrease of toxicity towards an alternative model (Artemia salina L.). These findings suggest that the NLS may be considered as a platform for incorporation of metallic complexes aimed at the treatment of TB. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Transition Metal Intercalators as Anticancer Agents—Recent Advances

by Krishant M. Deo, Benjamin J. Pages, Dale L. Ang, Christopher P. Gordon and Janice R. Aldrich-Wright

Int. J. Mol. Sci. 2016, 17(11), 1818; https://doi.org/10.3390/ijms17111818 - 31 Oct 2016

Cited by 67 | Viewed by 9704

Abstract

The diverse anticancer utility of cisplatin has stimulated significant interest in the development of additional platinum-based therapies, resulting in several analogues receiving clinical approval worldwide. However, due to structural and mechanistic similarities, the effectiveness of platinum-based therapies is countered by severe side-effects, narrow spectrum of activity and the development of resistance. Nonetheless, metal complexes offer unique characteristics and exceptional versatility, with the ability to alter their pharmacology through facile modifications of geometry and coordination number. This has prompted the search for metal-based complexes with distinctly different structural motifs and non-covalent modes of binding with a primary aim of circumventing current clinical limitations. This review discusses recent advances in platinum and other transition metal-based complexes with mechanisms of action involving intercalation. This mode of DNA binding is distinct from cisplatin and its derivatives. The metals focused on in this review include Pt, Ru and Cu along with examples of Au, Ni, Zn and Fe complexes; these complexes are capable of DNA intercalation and are highly biologically active. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model

by Atsushi Takeda, Haruna Tamano, Ryusuke Nishio and Taku Murakami

Int. J. Mol. Sci. 2016, 17(7), 1149; https://doi.org/10.3390/ijms17071149 - 16 Jul 2016

Cited by 15 | Viewed by 4748

Abstract

Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer’s disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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