Bioorganometallic Chemistry Research Articles

A multifaceted approach towards organometallic anticancer agent development

The approaches taken to develop novel metal-based anticancer agents have considerably changed over the last 50 years since the discovery of the platinum drugs and focus now on compounds that interact with proteins overexpressed in tumor cells, show novel modes of DNA interactions or accumulate with higher selectivity in tumors, to name a few. The structural diversity of anticancer agents has steadily increased and organometallic compounds are widely investigated. Over the years, bioorganometallic chemistry has developed into the thriving field of research it is today and in particular the development of anticancer agents with bioactive co-ligands coordinated to the metal center has received a lot of attention.In this personal perspective, I discuss concepts we use in anticancer metallodrug design and metallomics strategies to interrogate their modes of action. I focus on the impact of ligand structures on the biological activity of their organometallic complexes, complemented by observations of unexpected reactions and surprising behavior in the presence of biomolecules.

Coordination and Bioorganometallic Chemistry: Exploring the Potential Applications of Metal Coordination and Organometallic Complexes in Medical and Microbiological Advancements.

In the field of coordination and bioorganometallic chemistry, a notable shift is occurring. This mini-review explores a new generation of carefully 3D-crafted coordination and organometallic complexes that differ from conventional structures. Emphasizing disease intervention and microbial control, these compounds, incorporate noble and transition metals, and aim to enhance therapeutic efficacy while minimizing potential health risks. The mini-review covers diverse applications, showcasing their effectiveness against bacteria, viruses, fungi, and as potential tools in cancer treatment. Additionally, it sheds light on the inventive aspects of these complexes within biological systems. By highlighting advancements in bioorganometallic chemistry, the review offers insights and guidance for future developments in safer and more effective therapeutics.

From carbonyls to π-aromatic arenes: A thirty years journey through organometallic technetium chemistry

This account briefly summarizes the organometallic chemistry of technetium over the thirty years of experience made by the author and others. Earlier publications, many from the "Journal of Organometallic Chemistry", are included as well for showing that a careful reading of the "old" literature may influence actual chemistry, challenges and concepts, and the author's own research in particular. It is shown that kinetic differences between 99Tc and 99mTc lead to complexes not immediately envisaged under specific reaction conditions, but very useful for ultimate application in molecular imaging and bioorganometallic chemistry. As with many other d-elements, most of the organometallic chemistry is based on a few starting materials, e.g. binary carbonyls such as Tc2(CO)10, which is hardly available nowadays for different reasons. Still, there are ways around it to get to the same compounds as when starting from Tc2(CO)10. Organometallic technetium chemistry, a niche field, is still underdeveloped which is mirrored by the fact that some important core organometallics such as η2-alkene and η2-alkyne complexes, standard for other d-elements, are still missing.

Bioorganometallic chemistry – the early years

Bioorganometallic chemistry is now a maturing field attracting researchers around the world, and also across the Periodic Table. It has found applications in a broad range of areas such as drug discovery, biocatalysis and imaging. We review here the first experiments carried out in the early 1980′s at the Ecole Nationale Supérieure de Chimie de Paris under the leadership of Gérard Jaouen, a key figure and visionary in the development of this theme. However, they also required important contributions from Canadian collaborators with expertise in NMR and IR spectroscopy, together with the availability of more powerful and versatile instrumentation. This collaboration found its fulfillment in the demonstration of the use of metal carbonyl complexes (exemplified by an estradiol derivative labeled by a Cr(CO)3 unit) as non-isotopic tracers allowing the detection of estradiol receptors, an essential marker for setting up a targeted therapy for breast cancer. This approach was based on the premise that the intense metal carbonyl stretching vibrations are found in a window (2100–1850 cm−1) where the protein itself does not absorb. The field was extended to the arena of non-isotopic immunoassays, including the simultaneous detection of multiple antiepileptic drugs bearing metal carbonyl labels. More recently, taking advantage of the new technique of atomic force microscopy-infrared spectroscopy (AFM-IR) it has been possible to accomplish direct tracing of these complexes in cells. The contributions of the original group of workers in the field are highlighted, and placed in the perspective of today's subsequent emphasis on the management of previously untreatable cancers.

Has Ferrocene Really Delivered Its Role in Accentuating the Bioactivity of Organic Scaffolds?

Ferrocene is an important structural core in bioorganometallic chemistry because of its inherent stability, excellent redox properties, and low toxicity. Ferroquine and ferrocifen are two of the most notable contributions of ferrocene to medicinal chemistry with remarkable antimalarial and anticancer properties. The improved medicinal properties of these drug candidates highlight the impact that ferrocene can have on the molecular and biological properties of the bioactive compounds. In this Perspective, we investigate the scope and limitations of ferrocene incorporation into organic compounds/natural products on their mode of action and biological activities. We have also discussed the detailed role of ferrocene modifications in influencing the anticancer, antimalarial, and antimicrobial properties of various bioactive moieties to design safer and promising ferrocene-based drugs.

Computational Study of Bridge Splitting, Aryl Halide Oxidative Addition to PtII , and Reductive Elimination from PtIV : Route to Pincer-PtII Reagents with Chemical and Biological Applications.

Density functional theory computation indicates that bridge splitting of [PtII R2 (μ-SEt2 )]2 proceeds by partial dissociation to form R2 Pta (μ-SEt2 )Ptb R2 (SEt2 ), followed by coordination of N-donor bromoarenes (L-Br) at Pta leading to release of Ptb R2 (SEt2 ), which reacts with a second molecule of L-Br, providing two molecules of PtR2 (SEt2 )(L-Br-N). For R=4-tolyl (Tol), L-Br=2,6-(pzCH2 )2 C6 H3 Br (pz=pyrazol-1-yl) and 2,6-(Me2 NCH2 )2 C6 H3 Br, subsequent oxidative addition assisted by intramolecular N-donor coordination via PtII Tol2 (L-N,Br) and reductive elimination from PtIV intermediates gives mer-PtII (L-N,C,N)Br and Tol2 . The strong σ-donor influence of Tol groups results in subtle differences in oxidative addition mechanisms when compared with related aryl halide oxidative addition to palladium(II) centres. For R=Me and L-Br=2,6-(pzCH2 )2 C6 H3 Br, a stable PtIV product, fac-PtIV Me2 {2,6-(pzCH2 )2 C6 H3 -N,C,N)Br is predicted, as reported experimentally, acting as a model for undetected and unstable PtIV Tol2 {L-N,C,N}Br undergoing facile Tol2 reductive elimination. The mechanisms reported herein enable the synthesis of PtII pincer reagents with applications in materials and bio-organometallic chemistry.

Challenges in the Synthesis of Active Site Mimics for [NiFe]-Hydrogenases.

One of the more active areas in bioorganometallic chemistry is the preparation and reactivity studies of active site mimics of the [NiFe]-hydrogenases. One area of particular recent progress involves reactions that interconvert Ni(μ-X)Fe centers for X = OH, H, CO, as described by Song et al. Such reactions illustrate new ways to access intermediates related to the Ni-R and Ni-SI states of the enzyme. Most models are derivatives of the type (diphosphine)Ni(SR)2Fe(CO)3-n(PR'3)n. In recent work, the methodology has been generalized to include FeII(diphosphine) derivatives of Ni(N2S2), where N2S22- is the tetradentate diamine-dithiolate (CH2N(CH3)CH2CH2S-)2. Indeed, models based on Ni(N2S2) have proven valuable, but these studies also highlight challenges in working with heterobimetallic complexes, specifically the tendency of some such Ni-Fe complexes to convert to homometalliic Ni-Ni derivatives. This kind of problem is not readily detected by X-ray crystallography. With this caution in mind, we argue that one series of complexes recently described in this journal are almost certainly misassigned.

Metal‐Metal Interactions in Bi‐, Tri‐ and Multinuclear Fe, Ru and Os N‐Heterocyclic Carbene Complexes and their Catalytic Applications

AbstractN‐heterocyclic carbenes (NHCs) have been the focal point of advanced research on catalysis and bioorganometallic chemistry in the last decade. The field of NHC‐metal mediated catalysis has steadily grown over past years, commencing from the seminal discoveries on various C−C, C−N coupling and acceleration of C−H bond activation reactions. This review presents an overview of the work about the effects of NHC ligand field on metal‐metal contacts in Fe, Ru and Os metal NHC complexes. The influence of these contacts in making the supramolecular assemblies and their consequences on the reactivity patterns is reviewed. Correspondingly, the synergic effects between two metals leading to a unique reactivity pattern are correlated. The suitability and efficiency of various synthetic protocols used to prepare bi‐, tri‐ and multinuclear transition metal NHC complexes where metal‐metal contacts are possible, is discussed. Alternatively, this study on metal‐metal contacts in Fe, Ru and Os metal NHC complexes has great potential in the fields of homogeneous and heterogonous catalysis including the new designs for efficient hydrogen evolution electrocatalysts and oxidation and acylation catalysts. Rational ligand design leading to metal‐metal contacts by the appropriate functionalization of NHCs to investigate their applications in mentioned fields are thus fundamental to our efforts. Apart from their applications, the nature of the metal‐carbene carbon bond, nature of auxiliary ligand(s) and the influence of suitably functionalized NHC ligands led to generate advanced structural motifs have also been emphasized.

Gold Derivatives Development as Prospective Anticancer Drugs for Breast Cancer Treatment

Commonly used anticancer drugs are cisplatin and other platinum-based drugs. However, the use of these drugs in chemotherapy causes numerous side effects and the onset of frequent drug resistance phenomena. This review summarizes the most recent results on the gold derivatives used for their significant inhibitory effects on the in vitro proliferation of breast cancer cell models and for the consequences deriving from morphological changes in the same cells. In particular, the study discusses the antitumor activity of gold nanoparticles, gold (I) and (III) compounds, gold complexes and carbene-based gold complexes, compared with cisplatin. The results of screening studies of cytotoxicity and antitumor activity for the gold derivatives show that the death of cancer cells can occur intrinsically by apoptosis. Recent research has shown that gold (III) compounds with square planar geometries, such as that of cisplatin, can intercalate the DNA and provide novel anticancer agents. The gold derivatives described can make an important contribution to expanding the knowledge of medicinal bioorganometallic chemistry and broadening the range of anticancer agents available, offering improved characteristics, such as increased activity and/or selectivity, and paving the way for further discoveries and applications.

Bio-organometallic Peptide Conjugates: Recent Advances in Their Synthesis and Prospects for Biomedical Application

One area of organometallic chemistry that has attracted great interest in recent years is the syntheses, characterization and study of organometallic complexes conjugated to biomolecules with different steric and electronic properties as potential therapeutic agents against cancer and malaria, as antibiotics and as radiopharmaceuticals. This minireview focuses on the unique structural diversity that has recently been discovered in α- amino acids and the reactions of metallocene complexes with peptides having different chemical behavior and potential medical applications. Replacing α-amino acids with metallocene fragments is an effective way of selectively influencing the physicochemical, structural, electrochemical and biological properties of the peptides. Consequently, research in the field of bioorganometallic chemistry offers the opportunity to develop bioactive metal compounds as an innovative and promising approach in the search for pharmacological control of different diseases.

Recent Advances in the Biological Investigation of Organometallic Platinum-Group Metal (Ir, Ru, Rh, Os, Pd, Pt) Complexes as Antimalarial Agents.

In the face of the recent pandemic and emergence of infectious diseases of viral origin, research on parasitic diseases such as malaria continues to remain critical and innovative methods are required to target the rising widespread resistance that renders conventional therapies unusable. The prolific use of auxiliary metallo-fragments has augmented the search for novel drug regimens in an attempt to combat rising resistance. The development of organometallic compounds (those containing metal-carbon bonds) as antimalarial drugs has been exemplified by the clinical development of ferroquine in the nascent field of Bioorganometallic Chemistry. With their inherent physicochemical properties, organometallic complexes can modulate the discipline of chemical biology by proffering different modes of action and targeting various enzymes. With the beneficiation of platinum group metals (PGMs) in mind, this review aims to describe recent studies on the antimalarial activity of PGM-based organometallic complexes. This review does not provide an exhaustive coverage of the literature but focusses on recent advances of bioorganometallic antimalarial drug leads, including a brief mention of recent trends comprising interactions with biomolecules such as heme and intracellular catalysis. This resource can be used in parallel with complementary reviews on metal-based complexes tested against malaria.

A tutorial for the assessment of the stability of organometallic complexes in biological media

The use of metal-based drugs is increasingly gaining importance in medicine and renowned conferences such as the International Symposium on Bioorganometallic Chemistry (ISBOMC) are excellent opportunities for scientists in the field to exchange ideas and present their research on this topic. We decided to dedicate one of our group’s presentations at ISBOMC’19 to the detailed experimental description of the stability studies on metallocene-containing compounds that we are currently developing. The stability of (organometallic) drug candidates in biological media such as plasma is indeed a crucial parameter in medicinal chemistry and drug design. The presentation was very well received by the audience, which prompted us to contribute to this special issue with an article in the form of a tutorial. More specifically, we are aiming to show how such experiments can be easily performed in standard chemistry laboratories, without the need of specific pharmacological or biological expertise. In this tutorial article, we describe the detailed protocols for studies with human plasma and human microsomes, which simulate the conditions in the blood and liver, respectively, so that medicinal chemists from organometallic backgrounds can take the plunge without fear.

Luminescent Palladacycles Containing a Pyrene Chromophor; Synthesis, Biological and Computational Studies of the Interaction with DNA and BSA

AbstractOne of the most active areas within the field of bioorganometallic chemistry, complexes of N‐heterocyclic carbenes (NHCs), have recently gained interest. Herein, we report two luminescent palladium N‐heterocyclic carbene complexes; namely [Pd{(C,N)‐C6H4CH2NH(CH2CH3)}(1)] (2) and [Pd{(C,N)‐C6H4CH2NH2}(1)] (3) (1=1‐methyl‐3‐(2‐oxo‐2‐(pyren‐1‐yl)ethyl)‐2,3‐dihydroimidazol‐2‐ylidene) which were synthesized from the reaction of luminescent imidazolium salt (1(H)Br) and binuclear Palladacycles. The interactions of them with CT‐DNA evaluated via absorption, emission and CD spectral techniques as well as measurements of viscosity and thermal denaturation and the results have been shown that they bounded to CT‐DNA by intercalation and groove binding modes. The in vitro cytotoxicity of compounds 2–3 and 1(H)Br on human breast (MCF‐7) and cervical epithelial carcinoma (HeLa) cancer cells lines, indicated the wide range of anticancer activities of them with low IC50 values. Moreover, based on the protein binding ability studies, the intrinsic fluorescence of BSA could be strongly quenched by compounds via a static quenching mechanism. Competitive binding study using Eosin, Digoxin and Ibuprofen as site markers, indicated that the compounds could bind to sites I and II on BSA structure. Finally, all data obtained from biophysical studies were validated by molecular modeling study. Computational results showed that palladium complexes have the potential for detection of mismatch DNA.

N-Heterocyclic Carbene Complexes of Copper, Nickel, and Cobalt.

The emergence of N-heterocyclic carbenes as ligands across the Periodic Table had an impact on various aspects of the coordination, organometallic, and catalytic chemistry of the 3d metals, including Cu, Ni, and Co, both from the fundamental viewpoint but also in applications, including catalysis, photophysics, bioorganometallic chemistry, materials, etc. In this review, the emergence, development, and state of the art in these three areas are described in detail.

Chirality Induction in Bioorganometallic Conjugates

Considerable attention has been given to the research field of bioorganometallic chemistry, which is a hybrid chemistry field between biology and organometallic chemistry. The introduction of biomolecules, which have hydrogen bonding sites and chiral centers, into organometallic compounds is a promising strategy to construct chirality-organized bioorganometallic conjugates. This feature paper sketches an outline of induction of helical chirality into bioorganometallic conjugates by the control of a torsional twist of the organometallic moiety. Topics covered included control of the helical chirality of 1,n′-disubstituted ferrocene moieties in ferrocene-dipeptide conjugates, and the chirality induction of the Au(I)–Au(I) axis in the dinuclear organogold(I)-uracil conjugates.

Paradigm Shift for Radical S-Adenosyl-l-methionine Reactions: The Organometallic Intermediate Ω Is Central to Catalysis.

Radical S-adenosyl-l-methionine (SAM) enzymes comprise a vast superfamily catalyzing diverse reactions essential to all life through homolytic SAM cleavage to liberate the highly reactive 5′-deoxyadenosyl radical (5′-dAdo·). Our recent observation of a catalytically competent organometallic intermediate Ω that forms during reaction of the radical SAM (RS) enzyme pyruvate formate-lyase activating-enzyme (PFL-AE) was therefore quite surprising, and led to the question of its broad relevance in the superfamily. We now show that Ω in PFL-AE forms as an intermediate under a variety of mixing order conditions, suggesting it is central to catalysis in this enzyme. We further demonstrate that Ω forms in a suite of RS enzymes chosen to span the totality of superfamily reaction types, implicating Ω as essential in catalysis across the RS superfamily. Finally, EPR and electron nuclear double resonance spectroscopy establish that Ω involves an Fe–C5′ bond between 5′-dAdo· and the [4Fe–4S] cluster. An analogous organometallic bond is found in the well-known adenosylcobalamin (coenzyme B12) cofactor used to initiate radical reactions via a 5′-dAdo· intermediate. Liberation of a reactive 5′-dAdo· intermediate via homolytic metal–carbon bond cleavage thus appears to be similar for Ω and coenzyme B12. However, coenzyme B12 is involved in enzymes catalyzing only a small number (∼12) of distinct reactions, whereas the RS superfamily has more than 100 000 distinct sequences and over 80 reaction types characterized to date. The appearance of Ω across the RS superfamily therefore dramatically enlarges the sphere of bio-organometallic chemistry in Nature.

Application of organocatalysis in bioorganometallic chemistry: asymmetric synthesis of multifunctionalized spirocyclic pyrazolone–ferrocene hybrids as novel RalA inhibitors

Asymmetric construction of chiral spirocyclic pyrazolone–ferrocene hybrids has been developed. The lead compound displayed potent RalA inhibition.

Novel Gold and Silver Carbene Complexes Exert Antitumor Effects Triggering the Reactive Oxygen Species Dependent Intrinsic Apoptotic Pathway.

Cisplatin and other platinum-based drugs are well-known valid anticancer drugs. However, during chemotherapy, the presence of numerous side effects and the onset of frequent phenomena of resistance has pushed many research groups to devise new metal-based compounds holding improved anticancer properties and fewer undesired effects. Amongst the variety of synthesized compounds, significant antiproliferative effects have been obtained by employing organometallic compounds, particularly those based on silver and gold. With this in mind, we synthesized four compounds, two silver complexes and two gold complexes, with good inhibitory effects on the in vitro proliferation of breast and ovarian cancer-cell models. The antitumor activity of the most active compound, that is, AuL4, was found to be ninefold higher than that of cisplatin, and this compound induced dramatic morphological changes in HeLa cells. AuL4 induced PARP-1 cleavage, caspases 3/7 and 9 activation, mitochondria disruption, cytochrome c release in cancer-cell cytoplasm, and the intracellular production of reactive oxygen species. Thus, AuL4 treatment caused cancer-cell death by the intrinsic apoptotic pathway, whereas no cytotoxic effects were recorded upon treating non-tumor cell lines. The reported outcomes may be an important contribution to the expanding knowledge of medicinal bio-organometallic chemistry and enlarge the available anticancer toolbox, offering improved features, such as higher activity and/or selectivity, and opening the way to new discoveries and applications.

Design of prospective antiparasitic metal-based compounds including selected organometallic cores

Abstract A group of seventeen communicable and poverty-related diseases are considered neglected by the World Health Organization due to the restricted development of diagnostic methods, therapeutic treatments and/or control strategies. Among them three parasitic diseases caused by genetically related protozoa belonging to the trypanosomatid genus and kinetoplastida order are major health concerns in the developing world: American Trypanosomiasis (Chagas disease), Human African Trypanosomiasis and Leishmaniasis. This review focuses on efforts carried out to develop bioorganometallic compounds as prospective agents for the treatment of these diseases. It is divided in sections devoted to efforts grouped by type of organometallic core. Those series of compounds for which efforts have been done to modify structures through rational design, to get at least qualitative structure–activity relationships and to identify molecular targets and mode of action will be preferentially highlighted. Comments on potentialities, perspectives and tasks of bioorganometallic chemistry for the field of development of drugs against trypanosomatid parasites are also included.

Review on Bioorganometallic Chemistry and New Outcomes in the Synthesis and Substitution of Tetracarbonyl(pyrrolylimine) Complexes of Rhenium with Organophosphorus Ligands.

: After a short review dealing with bioorganometallic chemistry, the synthesis of tetracarbonyl (pyrrolylimine) complexes of rhenium bearing chirality on the pyrrolyl ligands was reported.The reactivity of these compounds towards the substitution of one carbonyl ligand with triphenyl phosphine, tricyclohexyl phosphine and trimethyl phosphite was studied. The rhenium becoming a stereogenic center in that transformation, the resulting tricarbonyl species were obtained as mixtures of diastereomers, with diastereomeric excesses varying from 8 to 84%, according to the reaction conditions and the relative steric hindrances of the pyrrolylimine and the organophosphorus ligands. These bioorganometallics are potential CO releasing molecules that could be used in the field of medicinal chemistry.