Ligand Exchange Properties Research Articles

Potential of organometallic complexes in medicinal chemistry

Abstract Organometallic complexes, which include ligands such as carbon monoxide (CO), carbenes, alkyls, phenyls, p-bound alkynes, alkenes, cyclopentadienyls, and arenes, have been extensively utilized in fields like materials chemistry and catalysis. These complexes also offer opportunities for the development of new medications with unique modes of action. Specifically, we are interested in anticancer drugs that can enhance the effectiveness of platinum treatments, broaden their range of action, reduce adverse effects, and prevent resistance. The distinct physiochemical properties of organometallic complexes have made them valuable in homogeneous catalysis, including the production of lead compounds and therapeutic possibilities. Over the past 20 years, a small group of researchers worldwide has explored the medical applications of these compounds’ unique characteristics, such as their structural diversity, potential for ligand exchange, and redox and catalytic properties. The results have been remarkable, and it is anticipated that numerous other organometallic compounds will undergo clinical trials in the coming years in addition to those already underway. In this brief study, we outline the advantages that organometallic metal complexes have over coordination compounds and pure organic molecules.

Universal, open MHC-I for rapid ligand loading and enhanced complex stability across classical and non-classical allotypes.

Abstract The instability of class I major histocompatibility complex (MHC-I) and MHC-like molecules loaded with suboptimal peptides, metabolites, or glycolipids presents an important biochemical challenge for identifying disease-relevant antigens and antigen-specific T cell receptors (TCRs) for autologous therapy development. Here, we leverage the coupled binding between ligand and the light chain (beta-2 microglobulin, β 2m) to the MHC-I heavy chain with the aim of developing conformationally stable molecules by engineering a disulfide bond to bridge the interface between the heavy and light chain. The resulting MHC-I molecules are stabilized in a ligand-receptive/open state, exhibit favorable ligand exchange properties, and are readily loaded with moderate affinity ligands to afford properly conformed protein complexes of enhanced stability compared to the wild type. We demonstrate the generality of the structural design using polymorphic HLA representatives covering multiple HLA-A and B supertypes, the nonclassical and oligomorphic HLA-Ib molecules, as well as MHC-like molecules, MR1 and CD1. Our platform allows spontaneous and rapid ligand exchange, which enables a range of approaches for ligand screening and the functional screening and characterization of polyclonal TCR repertoires. Supported by grants from NIH (R01AI143997, R35GM125034, U01DK112217).

Size Evolution Dynamics of Gold Nanoclusters at an Atom-Precision Level: Ligand Exchange, Growth Mechanism, Electrochemical, and Photophysical Properties

Interpretation of size evolution is an essential part of nanocluster transformation processes for unraveling the mechanism at an atom-precision level. Here we report the transformation of a non-superatomic Au23 to a superatomic Au36 nanocluster via Au28 cluster formation, activated by the bulky 4-tert-butylbenzenethiol ligand. Time-dependent matrix-assisted laser desorption ionization mass spectrometry data revealed that the conversion proceeds through ligand exchange followed by the size focusing method, ultimately leading to size growth. We also validated this transformation through time-dependent ultraviolet-visible data. Density functional theory calculations predicted that the kernel of the Au28 cluster evolved through a linear combination of molecular orbitals of the fragment of 2e- units (Au42+ and Au3+) from the kernel of the Au23 cluster. Periodic growth of gold cores through continuous growth of Au4 tetrahedral unit leads to the formation of the Au36 cluster from the Au28 cluster. These results reinforce the plausibility of size evolution through the growth mechanism during the transformation process. Differential pulse voltammetry studies showed that the highest occupied molecular orbital-lowest unoccupied molecular orbital gap inversely varies with the kernel size of these clusters. Photophysical experiments support the molecular-like intersystem crossing rather than core-shell relaxation to these clusters. The trends of photoluminescence lifetime were found to be the reverse of those of the energy gap law. The increment of lifetimes for the larger cluster can be mainly due to the contribution of both hot carriers and band-edge carriers.

From Catalysis to Cancer: Toward Structure-Activity Relationships for Benzimidazol-2-ylidene-Derived N-Heterocyclic-Carbene Complexes as Anticancer Agents.

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the RuII(arene) pharmacophore and even less with an OsII(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-CNHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η6-p-cymene)ruthenium(II) 1bI was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.

Anti-tumor activity of Organometallic Compounds

Modern medicine has been focusing on proving new and alternative chemotherapeutic compounds with high tumor cytotoxicity and reduced side effects to combat drug resistance and improve drug efficacy in cancer treatment. Organometallic compounds have unique physio-chemical properties like structural diversity, ligand exchange, redox and catalytic properties which are now being used to develop potential candidates for cancer therapy. The impressive clinical effectiveness of cisplatin is limited by the significant side effects and emergence of drug resistance. One of the metals showing promise is ruthenium. Ruthenium compounds often have lower cytotoxicity compared to cisplatin and are better tolerated in vivo. RuIII complexes maintain their metallic oxidation state till they reach the tumor, wherein a hypoxic condition is reduced to RuII. Moreover, in many cancer types, iron uptake is upregulated. Ruthenium, being in the same group as iron is transported into the cells by the transferrin receptor which is overexpressed in many tumors. Therefore, the properties of tumors enhance both Ru uptake and toxicity relative to normal tissues. DNA cleavage will lead to cell cycle arrest until the damage is repaired, or if it is too extensive to repair, it will undergo senescence and death that may be either dependent or independent of p53 tumor suppressor gene function. This project is focused on the synthesis, purification, and characterization of monometallic and bimetallic ruthenium compounds and evaluate its effects on glioblastoma, meningioma and pancreatic cell lines to analyze their effect on the proliferation of the tumor cells and their capacity to induce apoptosis.This project was supported by NIH Grants 5P20RR016477 and P20GM103434 to the West Virginia IDeA Network for BioMedical Research Funding.

Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors.

In recent years, the field of metal-based drugs has been dominated by other existing precious metal drugs, and many researchers have focused their attention on the synthesis of various ruthenium (Ru) complexes due to their potential medical and pharmaceutical applications. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidation states, low toxicity, high selectivity for diseased cells, ligand exchange properties, and the ability to mimic iron binding to biomolecules. In addition, Ru complexes have favorable adsorption properties, along with excellent photochemical and photophysical properties, which make them promising tools for photodynamic therapy. At present, nanostructured materials functionalized with Ru complexes have become an efficient way to administer Ru-based anticancer drugs for cancer treatment. In this review, the recent developments in the nanostructured materials functionalized with Ru complexes for targeted drug delivery to tumors are discussed. In addition, information on “traditional” (ie, non-nanostructured) Ru-based cancer therapies is included in a precise manner.

DNA interaction studies and photoinduced ligand exchange kinetics of a sterically strained ruthenium(II) complex

Sterically strained ruthenium polypyridyl complexes represent an emerging class of bioactive molecules, capable of photoinduced ligand exchange and covalent binding with DNA, in a manner similar to cisplatin. A sterically strained complex, [Ru(biq)2(dpp)](PF6)2, where biq=2,2′-biquinoline, dpp=2,3-bis(2-pyridyl)pyrazine, was synthesized, and investigated with respect to its photoinduced ligand exchange and DNA interaction properties. Although synthesis and redox properties of the complex, [Ru(biq)2(dpp)](PF6)2, have been reported, the photoinduced ligand exchange properties and DNA binding properties have not yet been reported. Photoinduced dissociation of the dpp ligand was observed upon irradiation of water or acetonitrile solutions of the metal complex with visible light (λirr⩾550nm) to generate [Ru(biq)2(H2O)2](PF6)2 and [Ru(biq)2(CH3CN)2](PF6)2 complexes, respectively. The half-lives of photoactivated exchange of the dpp ligand with water and acetonitrile were found to be 14min and 6min, respectively. The dissociation of the dpp ligand upon irradiation with light was confirmed by mass spectrometry. The synthesized complex displays covalent binding with DNA upon irradiation with visible light, confirmed by slowing down of the rate of DNA migration in agarose gel electrophoresis. No effect on the rate of migration of DNA was observed when incubated with metal complex in dark. The spectroscopic, photoinduced ligand exchange kinetics and DNA interaction properties are presented.

3d-4f {Co(II)3Ln(OR)4} Cubanes as Bio-Inspired Water Oxidation Catalysts.

Although the {CaMn4O5} oxygen evolving complex (OEC) of photosystem II is a major paradigm for water oxidation catalyst (WOC) development, the comprehensive translation of its key features into active molecular WOCs remains challenging. The [Co(II)3Ln(hmp)4(OAc)5H2O] ({Co(II)3Ln(OR)4}; Ln = Ho-Yb, hmp = 2-(hydroxymethyl)pyridine) cubane WOC series is introduced as a new springboard to address crucial design parameters, ranging from nuclearity and redox-inactive promoters to operational stability and ligand exchange properties. The {Co(II)3Ln(OR)4} cubanes promote bioinspired WOC design by newly combining Ln(3+) centers as redox-inactive Ca(2+) analogues with flexible aqua-/acetate ligands into active and stable WOCs (max. TON/TOF values of 211/9 s(-1)). Furthermore, they open up the important family of 3d-4f complexes for photocatalytic applications. The stability of the {Co(II)3Ln(OR)4} WOCs under photocatalytic conditions is demonstrated with a comprehensive analytical strategy including trace metal analyses and solution-based X-ray absorption spectroscopy (XAS) investigations. The productive influence of the Ln(3+) centers is linked to favorable ligand mobility, and the experimental trends are substantiated with Born-Oppenheimer molecular dynamics studies.

Density Functional Theory Studies on Structure, Ligand Exchange, and Optical Properties of Ligand-Protected Gold Nanoclusters: Thiolate versus Selenolate

Atomically precise thiolate-protected Au nanoclusters (NCs), i.e. Aum(SR)n, have attracted intensive research interest during the past few years. Recently, the synthesis and isolation of selenolate-protected gold clusters (Aum(SeR)n) via the ligand exchange of thiolate with selenol were achieved, which demonstrated identical compositions to those of thiolate-protected Au NCs. In this study, we perform a comprehensive theoretical study on the structure, electronic structure, and electronic optical absorption properties of 11 selenolate-protected gold clusters on the basis of density functional theory (DFT) calculations. Our results propose that the selenolate-protected Au NCs with framework structure identical to the thiolated ones are stable local minima. The ligand effect is proposed to understand the distinct geometrical structures of Au24(SeR)20 and Au24(SR)20 NCs. In addition, the optical absorption properties of thiolate- and selenolate-protected Au NCs are compared via the time-dependent density fun...

Organometallic compounds in cancer therapy: past lessons and future directions.

Over the past few years, modern medicinal chemistry has evolved towards providing us new and alternative chemotherapeutic compounds with high cytotoxicity towards tumor cells, alongside with reduced side effects in cancer patients. Organometallic compounds and their unique physic-chemical properties typically used in homogenous catalysis are now being translated as potential candidates for medical purposes. Their structural diversity, ligand exchange, redox and catalytic properties make them promising drug candidates for cancer therapy. Over the last decade this area has witnessed a steady growth and a few organometallic compounds have in fact already entered clinical trials, emphasizing its increasing importance and clinical relevance. Here we intend to stress out the different applications of organometallic compounds in medicine with emphasis on cancer therapy, as well as address setbacks regarding formulation issues, systemic toxicity and off-target effects. Advantages over classical coordination metal complexes, their nanovectorisation and specific molecular targets are also discussed.

Ligand-exchange dependent properties of hybrid nanocomposites based on luminescent colloidal CdSe nanocrystals in P3HT matrix

In this work, a suitable ligand-exchange process has been proposed which elucidates the possibility to modulate charge/energy transfer rate between polymer and semiconductor quantum dots. The photoluminescence studies of CdSe emission as well as transient absorption measurements confirm mainly electron transfer for P3HT:CdSe (TOPO) and electron/energy transfer for P3HT:CdSe (OA) nanocomposites, respectively. The dominance of charge transfer for P3HT:CdSe (TOPO) as compared to P3HT:CdSe (OA) nanocomposites can be attributed to complete and partial removal of the surface ligands (TOPO, OA) upon ligand exchange with pyridine as elucidated from FTIR results. The various characterization techniques viz. Fourier transform infrared (FTIR), Raman, photoluminescence (PL), optical and transient absorption (UV-Vis and TA) spectroscopies used in this work provide an insight into the charge separation, charge accumulation and/or trapping of charge carriers for the better understanding of hybrid organic-inorganic photovoltaics. Composites of CdSe (OA) quantum dots in particular with P3HT polymer owing to its higher crystallinity and ordered morphology provide a new and promising direction toward developing effective light energy harvesting strategies in organic photovoltaics.

Soluble Diamagnetic Model for Malaria Pigment: Coordination Chemistry of Gallium(III)protoporphyrin-IX

The facile axial ligand exchange properties of gallium(III) protoporphyrin IX in methanol solution were utilized to explore self-association interactions by NMR techniques. Structural changes were observed, as well as competitive behavior with the ligands acetate and fluoride, which differed from that seen with the synthetic analogue gallium(III) octaethylporphyrin which lacks acid groups in its side-chains and has less solution heterogeneity as indicated by absorption and MCD spectroscopies. The propionic acid side chains of protoporphyrin IX are implicated in all such interactions of PPIX, and both dynamic metal-propionic interactions and the formation of propionate-bridged dimers are observed. Fluoride coordination provides an unusual example of slow ligand exchange, and this allows for the identification of a fluoride bridged dimer in solution. An improved synthesis of the chloride and hydroxide complexes of gallium(III) protoporphyrin IX is reported. An insoluble gallium analogue of hematin anhydride is described. In general, the interactions between solvent and the metal are found to confer very high solubility, making [Ga(PPIX)](+) a useful model for ferric heme species.

The potential of organometallic complexes in medicinal chemistry

Organometallic complexes have unique physico-chemical properties, which have been widely used in homogenous catalysis, for example, for the synthesis of lead compounds and drug candidates. Over the past two decades, a few scientists from all over the world have extended the use of the specific characteristics of these compounds (e.g. structural diversity, possibility of ligand exchange, redox and catalytic properties) for medicinal purposes. The results are stunning. A few organometallic compounds have already entered clinical trials and it can be anticipated that several more will follow in coming years. In this short review, we present the specific advantages that organometallic metal complexes have over purely organic and also coordination compounds. Furthermore, using specific examples, we illustrate how these particular properties can be put to good use in medicinal chemistry. The examples we present have an emphasis on, but are not restricted to, anti-cancer activity.

An investigation into a cardiolipin acyl chain insertion site in cytochrome c

Mitochondrial cytochrome c associates with the phosphoplipid cardiolipin (CL) through a combination of electrostatic and hydrophobic interactions. The latter occurs by insertion into cytochrome c of an acyl chain, resulting in the dissociation of the axial Met-80 heme-iron ligand. The resulting five coordinate cytochrome c/CL complex has peroxidatic properties leading to peroxidation of CL and dissociation of the complex. These events are considered to be pre-apoptotic and culminate with release of cytochrome c from the mitochondria into the cytoplasm. Two distinct surface regions on cytochrome c have been suggested to mediate CL acyl chain insertion and this study has probed one of these regions. We have constructed a series of alanine mutants aimed at disrupting a surface cleft formed between residues 67–71 and 82–85. The physicochemical properties, peroxidase activity, CL binding, and kinetics of carbon monoxide (CO) binding to the ferrous cytochrome c/CL complex have been assessed for the individual mutants. Our findings reveal that the majority of mutants are capable of binding CL in the same apparent stoichiometry as the wild-type protein, with the extent to which the Met-80 ligand is bound in the ferrous cytochrome c/CL complex being mutant specific at neutral pH. Mutation of the species conserved Arg-91 residue, that anchors the cleft, results in the greatest changes to physicochemical properties of the protein leading to a change in the CL binding ratio required to effect structural changes and to the ligand-exchange properties of the ferrous cytochrome c/CL complex.

Titanium dioxide as chemo-affinity chromatographic sorbent of biomolecular compounds — Applications in acidic modification-specific proteomics

Characterization of the biomolecules involved in molecular processes occurring in biological systems such as the human cell remains central to biology, biotechnology, and medicine. One of the preferred methods of selectively purifying specific classes of biomolecules from complex biological matrices for further characterization is affinity chromatography, which relies on the specific interaction between an analyte in solution and a solid adsorbent. Titanium dioxide-based affinity chromatography has proven to be a versatile tool in enrichment of various compounds such as phosphorylated biomolecules due to its unique ion and ligand exchange properties and high stability towards pH and temperature. Recently, titanium dioxide chromatography was introduced in proteomics as a highly specific method for enriching phosphorylated peptides - a method, which has been widely adapted by the field of phosphoproteomics. Additional studies have shown the potential of this sorbent in purification of other acidic post-translational modified peptides, such as sialylated glycopeptides, thereby targeting the sialiome, defined as the content of sialic acid containing glycoproteins of a given cell, body fluid or tissue. The development of TiO(2)-based chromatographic strategies for separation of various biomolecules from its introduction for small molecules more than 20 years ago until recent proteomics applications today will be reviewed here.

Exposure-response of Cr(III)-organic complexes to Saccharomyces cerevisiae

Bioreduction of Cr (VI)to less toxic and less mobile Cr(lII)is considered to be a viable clean up option.Cr(VI) bioreduction also produces soluble Cr(IlI)-organic complexes with insoluble Cr(IlI)compounds.Though little is known about the fate and behaviour of soluble Cr-Ⅲ-organic in the environment,it is reported that once Cr-(III)-organic complexes are formed,they are relatively stable,due to the slow ligand exchange properties of Cr(III).There is no reported data about the toxicity of the Cr-(III)-organic complexes.The aim of this current research is to investigate the bioavailability and toxicity of the soluble Cr-III-organic complexes.For the experimental purpose Saccharomyces cereviciae L-1 wild type yeast strain was chosen as model organism and Cr-Ⅲ-citrate was selected as the representative compound of the Cr-(Ⅲ)-organic complexes.Growth inhibition,direct viable cell count,dry biomass,biosorption as well as the amount of CO2 production were measured to explore the potential for short-term chronic aquatic toxicity tests of the Cr-(Ⅲ)-citrate.Cr-(Ⅲ)-citrate exerted the tOxicity with an EC50,calculated from the％growth inhibition,of 51.03 mg/L.These toxicity data would be helpful to define the toxic potential of the organo-chromium-III compounds in the environment.

PL. Plenary lectures

Research during the 54 years since the discovery of non-heme iron oxygenase enzymes has revealed a remarkable diversity in the strategies used for O2 activation. Many of these are represented in dioxygenase enzymes that introduce oxygen atoms from O2 into aromatic compounds (1). These include direct oxygen activation by external electron transfer to the redox-active mononuclear iron in Rieske dioxygenases, Fe(II)-mediated internal electron transfer from the substrate to O2 in extradiol dioxygenases, and Fe(III)-mediated spin inversion during internal electron transfer from substrate to O2 in intradiol dioxygenases. Recently, the exploration of these mechanisms has moved forward through the combined use of transient kinetics, spectroscopic characterizations, high level computations, and X-ray crystallographic techniques that allow the visualization of discrete intermediates. For each enzyme class, catalysis is found to depend on an elegant balance between the Lewis acidity, redox, and ligand exchange properties of the metal, the traditional structural and catalytic properties of the second sphere residues of the active site, and the less-appreciated contributions from structural dynamics that encompass the entire enzyme. Together, these mediate not only specific catalysis, but just as importantly, regulated catalysis that mitigates against the activation of O2 without attendant substrate oxygenation.

Carbohydrate-Metal Complexes and their Potential as Anticancer Agents

Platinum complex-based chemotherapy is one of the major treatment options of many malignancies. Although severe side effects occur, and only a limited spectrum of tumors can be cured, Pt compounds are used in every second therapy scheme. Thus, many different drug design strategies have been employed for improving the properties of anticancer drugs including pH or redox activation in the tumor, variation of the metal center and therefore the redox and ligand exchange properties, the application of multinuclear metal complexes, the development of targeted approaches, etc. Application of carbohydrate-metal complexes is an example of a targeted approach exploiting the biochemical and metabolic functions of diverse sugars in living organisms for transport and accumulation. Natural carbohydrates and synthetic derivatives possess a manifold of donors endowing them with the ability to coordinate metal centers and providing some additional advantages over other ligands, e.g., biocompatibility, non-toxicity, enantiomeric purity, water solubility, and well-explored chemistry. In recent years, several examples of carbohydrate compounds have been developed for diverse medicinal applications ranging from compounds with antibiotic, antiviral, or fungicidal activity and anticancer compounds. Herein, metal complexes with carbohydrate ligands are reviewed and the role of the carbohydrate carriers on the antineoplastic activity of these compounds, both in vitro and in vivo, is described.

The water-soluble cluster cation [H3Ru3(C6H6)(C6Me6)2(O)]+: Improved synthesis, aerobic oxidation, electrochemical properties and ligand exchange studies

The synthesis of the trinuclear cluster cation [H3RU3(C6H6)(C6Me6)(2)(O)](+) (1) has been considerably improved by changes in the NaBH4 addition step and by introducing chromatographic methods; in addition, the redox and ligand exchange properties of 1 have been studied. Although exposure of ail aqueous solution of 1 to air yields the oxidised cluster [H2RU3(C6H6)(C6Me6)(2)(O)(OH)](+) (2), cyclic voltammetry of [1][BF4] in acetonitrile reveals a first reversible oxidation step that does not involve 2. Bulk electrolysis of I and 2 in the same medium affords only decomposition products. Ligand exchange in I takes place only at higher temperatures: by heating a mixture of toluene with ail aqueous solution of [1][BF4] (1000: 1) to 110 degrees C for 2 h, the formation of the toluene derivative [H3RU3(C6H5Me)(C6Me6)(2)(O)](+) (3) is observed in small quantities. H/D exchange of 1 with D2O does not occur up to 90 degrees C however, in the presence of D-2, H/D exchange with 1 is observed to give the deuterated derivative [D3RU3(C6H6)(C6Me6)(2)(O)](+) (1a). The results provide ail improved synthesis of 1, as well as information about its redox and ligand-exchange reactions, results necessary to understand and develop the chemistry of 1.

Critical flocculation concentrations, binding isotherms, and ligand exchange properties of peptide-modified gold nanoparticles studied by UV-visible, fluorescence, and time-correlated single photon counting spectroscopies.

Protocols for modifying gold nanoparticles with peptide-bovine serum albumin (BSA) conjugates are described within. The resulting constructs were characterized using a number of techniques including static fluorescence spectroscopy and time-correlated single photon counting spectroscopy (TCSPC) in order to quantify peptide-BSA binding isotherms, exchange rates, critical flocculation concentrations, and the composition of mixed peptide-BSA monolayers on gold nanoparticles. TCSPC has proven to be a powerful technique for observing the microenvironment of protein-gold nanoparticle conjugates because it can distinguish between surface-bound and solution-phase species without the need for separation steps. Full characterization of the composition and stability of peptide-modified metal nanoparticles is an important step in their use as intracellular delivery vectors and imaging agents.