Medicinal Inorganic Chemistry Research Articles

SÍNTESE E CARACTERIZAÇÃO DE COMPLEXOS DE COBALTO (II) COM LIGANTES ORGÂNICOS E AVALIAÇÃO ANTIMICROBIANA

A Química Inorgânica Medicinal é uma das áreas da Química de Coordenação que vem apresentando avanços na elucidação de novos fármacos com atividade biológica oriundos de complexos metálicos. Diante disso, o presente estudo teve como objetivos sintetizar dois complexos de cobalto com os ligantes 1-(1-feniletilideno)Carbonohidrazida (LDC) e com o ligante 1,10-Fenantrolina, realizar as caracterizações espectroscópicas e termogravimétrica, assim como, avaliar a atividade antibacteriana do ligante e dos complexos frente à bactéria Escherichia coli. Realizou-se a síntese de dois complexos a partir da adaptação da rota sintética disponível na literatura. Os complexos obtidos foram caracterizados por espectroscopia na região do Ultravioleta-Visível, bem como, pela Espectroscopia no Infravermelho e pela Termogravimetria. A atividade biológica ocorreu in vitro pelo método de difusão em disco, frente a cepa bacteriana Escherichia coli. O LDC apresentou duas bandas na região do ultravioleta (180 nm – 380 nm), não sendo verificadas absorções na região do visível (380 nm – 780 nm), pois o composto não apresentou cor. Verificou-se que na região do infravermelho, a banda dos complexos é deslocada para região de maior energia (maior número de onda), isso indica que o íon metálico esteja coordenado ao oxigênio da C=O. As avaliações termogravimétricas permitiram indicar a real composição dos complexos sintetizados. O ligante não apresentou inibição diante da bactéria, o complexo I e o complexo II demonstraram atividade frente à cepa bacteriana.

New Palladium(II), Platinum(II) and Silver(I) complexes of 2-amino-4,6-dithio-1,3,5-triazine; synthesis, characterization and DNA binding properties

Inorganic medicinal chemistry has been focused for many years on the study of the anticancer activity of transition metal complexes, especially those based on the Pt(II) ion. Since the 1,3,5-triazine molecule has significant biological activity, we thought that the development of new metallo-chemotherapeutic agents involving the triazine moiety might be of interest. With this in mind, we have now synthesized several mixed-ligand transition metal complexes with the 2-amino-4,6-dithio-1,3,5-triazine (Hat) ligand that also contain 2,2'bipyridine (bpy), 1,10-phenanthroline (phen) or triphenylphosphine (PPh3) as a secondary ligand. On the basis of various spectral [IR, NMR (1H, 13C, 31P), UV–vis and EI-mass] measurements and other physical analyses (molar conductivity, elemental analysis and TGA), two modes of coordination are proposed for the Hat ligand. The first is a neutral bidentate mode through either the amino-N(2) and cyclic-N(3) atoms or the thione-S(4) and cyclic-N(3) atoms. The second mode is a mononegative bidentate one via the deprotonated cyclic-N(1) atom and either the amino-N(2) or the thione-S(6) atom. The dissociation constant of Hat, as well as the stoichiometries and the formation constants of Co(II), Ni(II), Cu(II), Zn(II), Pd(II), Pt(II), [M(L)Cl2] (L = bpy, 2PPh3) and Ag(I) complexes in saline solution (pH 7.4), have been determined using both Job's and the molar ratio methods. The calf thymus (CT-DNA)-binding properties of several of the complexes have been determined using UV–vis spectroscopy. The binding constants (Kb) of the CT-DNA complexes indicate their high to moderate binding abilities, which may be the result of steric hindrance around the metal ions owing to the presence of the bulky bpy or PPh3 ligands.

Metalloproteomics for Unveiling the Mechanism of Action of Metallodrugs.

The clinical application and development of potent metal-based drugs relies heavily on a full understanding of their underlying molecular mechanisms. The emerging research field of metalloproteomics for unveiling the correlation between metals and biological proteomes has received growing attention and has been successfully implemented in medicinal inorganic chemistry. In this article, we introduce recent progress in the mechanistic studies of representative metal-based drugs by using state-of-the-art metalloproteomic approaches, with a focus on how the application of analytical chemistry, biocompatible chemical probes, and integrative omics help to advance the knowledge of metallodrug targeting profiles within a systemic perspective.

Metal Complexes in Medicine: An Overview and Update from Drug Design Perspective

Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Transition metal complexes are important in catalysis, materials synthesis, photochemistry, and biological systems. Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. The use of metals and their salts for medicinal purposes has been present throughout history. With the advancement in the field of inorganic chemistry the role of transition metal complexes as therapeutic compounds is becoming increasingly important. Recent advances in inorganic chemistry have made possible formation of number of transition metal complexes with organic ligand of interest, which can be used as therapeutic agent. This review illustrates the role of metals and the recent progress in the field of medicinal bioinorganic chemistry with new approaches to the design of innovative metal-based drugs and their application.

NAMI-A and KP1019/1339, Two Iconic Ruthenium Anticancer Drug Candidates Face-to-Face: A Case Story in Medicinal Inorganic Chemistry.

NAMI-A ((ImH)[trans-RuCl4(dmso-S)(Im)], Im = imidazole) and KP1019/1339 (KP1019 = (IndH)[trans-RuCl4(Ind)2], Ind = indazole; KP1339 = Na[trans-RuCl4(Ind)2]) are two structurally related ruthenium(III) coordination compounds that have attracted a lot of attention in the medicinal inorganic chemistry scientific community as promising anticancer drug candidates. This has led to a considerable amount of studies on their respective chemico-biological features and to the eventual admission of both to clinical trials. The encouraging pharmacological performances qualified KP1019 mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers, whereas the non-cytotoxic NAMI-A has gained the reputation of being a very effective antimetastatic drug. A critical and strictly comparative analysis of the studies conducted so far on NAMI-A and KP1019 allows us to define the state of the art of these experimental ruthenium drugs in terms of the respective pharmacological profiles and potential clinical applications, and to gain some insight into the inherent molecular mechanisms. Despite their evident structural relatedness, deeply distinct biological and pharmacological profiles do emerge. Overall, these two iconic ruthenium complexes form an exemplary and unique case in the field of medicinal inorganic chemistry.

THIOSEMICARBAZONE COMPLEXES AS VERSATILE MEDICINAL CHEMISTRY AGENTS: A REVIEW

Objective: Thiosemicarbazones are Schiff based ligands of significant biological importance and their biological relevance has been studied for a considerable amount of time period. When the thiosemicarbazones bind with metal ions, they have shown an array of potential anticancer, antimicrobial and antioxidant activities etc. They have also found numerous applications in Analytical Chemistry. This present review summarizes some of the medicinal benefits of thiosemicarbazone based complexes especially with transition metals. Data Sources: The studies cited in the present review were sourced from journals, books and conference proceedings preferentially written and published in English. Literature from the past 15 years or so has been included in the article. Papers indexed in known databases such as PUBMED, SCOPUS, INDEX COPERNICUS, CHEMICAL AND BIOLOGICAL ABSTRACTS, MEDLINE, EMBASE, EBSCO, DOAJ, and THOMSON REUTERS have been reviewed and included. Summary of the contents of the article: The study unravels the mechanistic action of these compounds on in vitro living beings viz. cell culture as well as animal models. An elaborate review of the available literature on thiosemicarbazones has shown that the modifications in the ligand moiety leads to enhancement in its activity and some of the best structural alterations have been cited in the review. Some of the potential future applications and uses of the complexes have also been discussed. Structure optimization of the compounds may result in path breaking finding of potential anticancer and antimicrobial drugs. Conclusion: Latest advances in medicinal inorganic chemistry have given considerable importance to the development of metal based drugs with thiosemicabazones. The presence of metal ion in the drug moiety usually mitigates the ill effects of the compounds, this may lead to the production of new metal based drugs. The key factors identified for their action has been the inhibition of RR, topo II and the production of ROS, but identification of other probable targets need to be explored.

Synthesis, Characterization and Cytotoxic Activity of N-(5-indanyl(methylene)anthranilic acid(5-indanyl methylene)-hydrazide and Its Pt(II) Complex

Since the discovery of the platinum based complex, cisplatin, medicinal inorganic chemistry has attracted much more attention and a large number of platinum complexes with promising pharmacological properties have been synthesized. In this work a new platinum complex of N-(5-indanyl(methylene)anthranilic acid(5-indanyl methylene)-hydrazide (HL) has been synthesized and characterized by physical and spectral techniques, as elemental analysis, IR, EI-MS, 1H-NMR, thermal analysis, transmittance electron microscope (TEM) and magnetic moment. The results indicated that the ligand binds to Pt(II) in the enol form. Square-planar stereochemistry was suggested for the Pt(II) complex. The morphological characterization showed nano-sized spherical particles with average size 92 nm of the isolated complex. The synthesized Pt(II) complex exhibited a significant cytotoxic activity against HCT116 and HEPG2. Also in vivo study of the Pt(II) complex showed cytotoxic activity towards Ehrlich ascites carcinoma (EAC).

Frontispiece: Catalysis Concepts in Medicinal Inorganic Chemistry

Frontispiece: Catalysis Concepts in Medicinal Inorganic Chemistry

Development and future prospects of selective organometallic compounds as anticancer drug candidates exhibiting novel modes of action

Organometallic complexes have widely been used for the treatment of various diseases viz., malaria, arthritis, syphilis, pernicious anemia, tuberculosis and particular in cancers. Recent decades have witnessed an upsurging interest in the application of organometallic compounds to treat various phenotypes of cancers with multiple etiologies. The unique and exceptional properties of organometallic compounds, intermediate between classical inorganic and organic materials provide new insight in the progress of inorganic medicinal chemistry. Herein, we have selectively focused on various organometallic sandwich and half-sandwich complexes of ruthenium (Ru), titanium (Ti), gold (Au) and iron (Fe) exhibiting promising activity towards a panel of cancer cell lines and resistant cancer cell lines. These complexes exhibit novel mechanisms of drug action through incorporation of outer-sphere recognition of molecular targets and controlled activation features based on ligand substitution along with monometallic and heterometallic redox processes. Furthermore, they are usually found to be uncharged or neutral possessing metals in a low oxidation state, exhibit kinetic stability, relative lipophilicity and are amenable to a host of various chemical transformations. This review mainly sheds light on the successful advancement of organometallic complexes as anticancer drug aspirants in relation to their versatile structural chemistry and innovative mechanisms of action targeting nucleic acids, several enzymes viz; thioredoxin reductases (Thrx), EGFR, transferrin, cathepsin B, topoisomerases etc.

Catalysis Concepts in Medicinal Inorganic Chemistry.

Catalysis has strongly emerged in the field of medicinal inorganic chemistry as a suitable tool to deliver new drug candidates and to overcome drawbacks associated to metallodrugs. In this Concept article, we discuss representative examples of how catalysis has been applied in combination with metal complexes to deliver new therapy approaches. In particular, we explain key achievements in the design of catalytic metallodrugs that damage biomolecular targets and in the development of metal catalysis schemes for the activation of exogenous organic prodrugs. Moreover, we discuss our recent discoveries on the flavin-mediated bioorthogonal catalytic activation of metal-based prodrugs; a new catalysis strategy in which metal complexes are unconventionally employed as substrates rather than catalysts.

The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss.

Extraordinary progress in medicinal inorganic chemistry in the past few years led to the rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. To overcome poor solubility and toxicity problems that limited the application of these compounds numerous delivering systems were used (Lila et al. in Biol Pharm Bull 37:206-211, 2014; Yue and Cao in Curr Cancer Drug Targets 16:480-488, 2016; Duan et al. in WIREs Nanomed Nanobiotechnol 8:776-791, 2016). Regarding high drug loading capacity, mesoporous silica nanoparticles like SBA-15 became more important for targeted drug delivery. In this study, cellular uptake and biological activities responsible for organotin(IV) compound Ph3Sn(CH2)6OH (Sn6) grafted into (3-chloropropyl)triethoxysilane functionalized SBA-15 (SBA-15p → SBA-15p|Sn6) were evaluated in human melanoma A375 cell line. Moreover, the influence of SBA-15p grafted with organotin(IV) compound on the stemness of A375 cell was tested. Given the fact that SBA-15p|Sn6 nanoparticles are nonspherical and relatively large, their internalization efficiently started even after 15min with stable adhesion to the cell membrane. After only 2h of incubation of A375 cells with SBA-15p|Sn6 passive fluid-phase uptake and macropinocytosis were observed. Inside of the cell, treatment with SBA-15p loaded with Sn6 promoted caspase-dependent apoptosis in parallel with senescence development. The subpopulation of cells expressing Schwann-like phenotype arose upon the treatment, while the signaling pathway responsible for maintenance of pluripotency and invasiveness, Wnt, Notch1, and Oct3/4 were modulated towards less aggressive signature. In summary, SBA-15p enhances the efficacy of free Sn6 compound through efficient uptake and well profiled intracellular response followed with decreased stem characteristics of highly invasive A375 melanoma cells.

Toward Multi-Targeted Platinum and Ruthenium Drugs-A New Paradigm in Cancer Drug Treatment Regimens?

While medicinal inorganic chemistry has been practised for over 5000 years, it was not until the late 1800s when Alfred Werner published his ground-breaking research on coordination chemistry that we began to truly understand the nature of the coordination bond and the structures and stereochemistries of metal complexes. We can now readily manipulate and fine-tune their properties. This had led to a multitude of complexes with wide-ranging biomedical applications. This review will focus on the use and potential of metal complexes as important therapeutic agents for the treatment of cancer. With major advances in technologies and a deeper understanding of the human genome, we are now in a strong position to more fully understand carcinogenesis at a molecular level. We can now also rationally design and develop drug molecules that can either selectively enhance or disrupt key biological processes and, in doing so, optimize their therapeutic potential. This has heralded a new era in drug design in which we are moving from a single- toward a multitargeted approach. This approach lies at the very heart of medicinal inorganic chemistry. In this review, we have endeavored to showcase how a "multitargeted" approach to drug design has led to new families of metallodrugs which may not only reduce systemic toxicities associated with modern day chemotherapeutics but also address resistance issues that are plaguing many chemotherapeutic regimens. We have focused our attention on metallodrugs incorporating platinum and ruthenium ions given that complexes containing these metal ions are already in clinical use or have advanced to clinical trials as anticancer agents. The "multitargeted" complexes described herein not only target DNA but also contain either vectors to enable them to target cancer cells selectively and/or moieties that target enzymes, peptides, and intracellular proteins. Multitargeted complexes which have been designed to target the mitochondria or complexes inspired by natural product activity are also described. A summary of advances in this field over the past decade or so will be provided.

Molecular methods for assessment of non-covalent metallodrug-DNA interactions.

The binding of small molecule metallodrugs to discrete regions of nucleic acids is an important branch of medicinal chemistry and the nature of these interactions, allied with sequence selectivity, forms part of the backbone of modern medicinal inorganic chemistry research. In this tutorial review we describe a range of molecular methods currently employed within our laboratories to explore novel metallodrug-DNA interactions. At the outset, an introduction to DNA from a structural perspective is provided along with descriptions of non-covalent DNA recognition focusing on intercalation, insertion, and phosphate binding. Molecular methods, described from a non-expert perspective, to identify non-covalent and pre-associative nucleic acid recognition are then demonstrated using a variety of techniques including direct (non-optical) and indirect (optical) methods. Direct methods include: X-ray crystallography; NMR spectroscopy; mass spectrometry; and viscosity while indirect approaches detail: competitive inhibition experiments; fluorescence and absorbance spectroscopy; circular dichroism; and electrophoresis-based techniques. For each method described we provide an overview of the technique, a detailed examination of results obtained and relevant follow-on of advanced biophysical/analytical techniques. To achieve this, a selection of relevant copper(ii) and platinum(ii) complexes developed within our laboratories are discussed and are compared, where possible, to classical DNA binding agents. Applying these molecular methods enables us to determine structure-activity factors important to rational metallodrug design. In many cases, combinations of molecular methods are required to comprehensively elucidate new metallodrug-DNA interactions and, from a drug discovery perspective, coupling this data with cellular responses helps to inform understanding of how metallodrug-DNA binding interactions manifest cytotoxic action.

Development and Validation of Liquid Chromatography-Based Methods to Assess the Lipophilicity of Cytotoxic Platinum(IV) Complexes

Lipophilicity is a crucial parameter for drug discovery, usually determined by the logarithmic partition coefficient (Log P) between octanol and water. However, the available detection methods have restricted the widespread use of the partition coefficient in inorganic medicinal chemistry, and recent investigations have shifted towards chromatographic lipophilicity parameters, frequently without a conversion to derive Log P. As high-performance liquid chromatography (HPLC) instruments are readily available to research groups, a HPLC-based method is presented and validated to derive the partition coefficient of a set of 19 structurally diverse and cytotoxic platinum(IV) complexes exhibiting a dynamic range of at least four orders of magnitude. The chromatographic lipophilicity parameters φ0 and Log kw were experimentally determined for the same set of compounds, and a correlation was obtained that allows interconversion between the two lipophilicity scales, which was applied to an additional set of 34 platinum(IV) drug candidates. Thereby, a φ0 = 58 corresponds to Log P = 0. The same approaches were successfully evaluated to determine the distribution coefficient (Log D) of five ionisable platinum(IV) compounds to sample pH-dependent effects on the lipophilicity. This study provides straight-forward HPLC-based methods to determine the lipophilicity of cytotoxic platinum(IV) complexes in the form of Log P and φ0 that can be interconverted and easily expanded to other metal-based compound classes.

A gold(i) biscarbene complex with improved activity as a TrxR inhibitor and cytotoxic drug: comparative studies with different gold metallodrugs.

Gold complexes with N-heterocyclic carbene (NHC) ligands have been attracting major attention in medicinal inorganic chemistry based on their favorable antiproliferative effects and the structural versatility of the coordinated NHC ligands. Here we present a novel complex of the type (NHC)2Au+, which represents a substantially improved and selective TrxR inhibitor compared to close structural analogues. The complex is highly stable in various solutions over 96 hours, however, comparative cellular uptake studies indicate metabolic transformations inside cells over time. A portfolio of other gold complexes (e.g. Auranofin) has been used as references in key biological assays, showing that the novel (NHC)2Au+ complex exhibits substantially lower protein binding in combination with a strongly enhanced cytotoxic activity.

Targeting the Folate Receptor: Improving Efficacy in Inorganic Medicinal Chemistry

The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor's overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting. The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established. The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach. From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis. The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis. In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes. We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity. The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics.

Self-Assembled Multinuclear Complexes Incorporating 99m Tc.

Multinuclear complexes or clusters are rarely investigated in medicinal inorganic chemistry although they represent structural intermediates between molecules and nanomaterials. We present in this report two strategies towards 99m Tc-containing clusters. In a pre-assembly approach, the preformed but incomplete cluster fragment [Re3 (μ2 -OH)3 (μ3 -OH)(CO)9 ]- reacts with [99m Tc(CO)3 ]+ to the highly stable [99m TcRe3 (μ3 -OH)4 (CO)12 ] cube. The same structure self-assembles when reacting the mononuclear Re and 99m Tc precursors in one pot. Integrating the coordinating OH groups from Schiff bases in this concept leads straight to dinuclear, mixed-metal complexes of the type [99m TcRe(μ2 -O^N-R1 )2 (CO)6 ] in quantitative yields. Both strategies are unprecedented and open a future path towards clusters, incorporating a 99m Tc radiolabel while being decorated with targeting or cytotoxic moieties.

Metal Complexes as Potential Antimicrobial Agent: A Review

Metal ions play many critical functions in humans. Deficiency of some metal ions can lead to disease like pernicious anemia resulting from iron deficiency, growth retardation arising from insufficient dietary zinc, and heart disease in infants owing to copper deficiency. Antibiotic resistance has been growing at an alarming rate and consequently the activity of antibiotics against Gram-negative and Gram-positive bacteria has dropped dramatically day by day. In this sense there is a strong need to synthesis new substances that not only have good spectrum of activity, but having new mechanisms of action. Inorganic compounds particularly metal complexes have played an important role in the development of new metal based drugs. A significantly rising interest in the design of metal complexes as drugs and diagnostic agents is currently observed in the area of scientific inquiry, specifically termed medicinal inorganic chemistry. In this review our main focused on research undertaken over the past few decades which has sought to possess preclinical pharmacological screenings like anti-bacterial, anti-fungal, anti-inflammatory, anti-cancer, DNA- interaction and anti-tumor action of synthetic metal complexes.

The antioxidant 2,6-di-tert-butylphenol moiety attenuates the pro-oxidant properties of the auranofin analogue.

Metal-based drugs are gaining momentum as a rapidly developing area of medicinal inorganic chemistry. Among gold pharmaceuticals, auranofin is a well known antirheumatic drug. The efficacy of gold-organic complexes largely depends on their pro-oxidant properties since auranofin targets the redox enzyme thioredoxin reductase (TrxR). However, an uncontrollable oxygen burst may be harmful for healthy cells; therefore, the search for chemical modifications to attenuate oxidation-related general toxicity of gold containing anti-inflammatory drugs is justified. In this study, we demonstrate that the incorporation of a specific antioxidant phenol fragment can counterbalance the pro-oxidative potential of the Au containing complex molecule. The electrochemical studies of AuPPh3SR (1, R= 3,5-di-tert-butyl-4-hydroxyphenyl) and its precursors AuPPh3Cl (2) and RSH (3) showed that complex 1 and phenol 3 efficiently scavenged the radicals (as detected by cyclic voltammetry) whereas 2 had no effect. Compound 1 inhibited TrxR in vitro with IC50 0.57 ± 0.15 μM, a value one order of magnitude bigger than the potency reported for auranofin. Compound 1 (5 mg kg-1 daily gavage for 14 days) caused a decrease in ex vivo spontaneous and ascorbate-induced lipid peroxidation in the homogenates of rat lung, heart muscle, spleen, liver, kidneys, testicles and brain as assessed by the thiobarbituric acid reactive substances. Importantly, in animals fed with 1, no discernible general toxicity was registered suggesting that this compound is well tolerated. Our results provide evidence for an efficient synthetic route to obtain gold containing anti-inflammatory drug candidates with balanced pro/anti-oxidative properties.

Pre-/post-functionalization in dipyrrin metal complexes - antitumor and antibacterial activity of their glycosylated derivatives.

A post-functionalization route to tris(dipyrrinato) metal complexes is presented giving access to a range of new complexes relevant in the context of medicinal inorganic chemistry. A pentafluorophenyl group in the meso-position of the dipyrrin ligand serves as an anchor for the connection with alcohols and thiocarbohydrates. The photochemotherapeutic activity of the complexes has been assessed in cellular assays with tumor cell lines and against the Gram-positive bacterium S. aureus. Finally, it is shown that this post-functionalization is also applicable to other dipyrrinato metal complexes.