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Molecules (Basel, Switzerland) Jan 2021Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a... (Review)
Review
Reactions of cyclometalated compounds are numerous. This account is focused on one of such reactions, the exchange of cyclometalated ligands, a reaction between a cyclometalated compound and an incoming ligand that replaces a previously cyclometalated ligand to form a new metalacycle: + H-C*~Z ⇄ + H-C~Y. Originally discovered for Pd complexes with Y/Z = N, P, S, the exchange appeared to be a mechanistically challenging, simple, and convenient routine for the synthesis of cyclopalladated complexes. Over four decades it was expanded to cyclometalated derivatives of platinum, ruthenium, manganese, rhodium, and iridium. The exchange, which is also questionably referred to as transcyclometalation, offers attractive synthetic possibilities and assists in disclosing key mechanistic pathways associated with the C-H bond activation by transition metal complexes and C-M bond cleavage. Both synthetic and mechanistic aspects of the exchange are reviewed and discussed.
Topics: Ligands; Metals; Molecular Structure; Organometallic Compounds
PubMed: 33401624
DOI: 10.3390/molecules26010210 -
Science Progress 2014Metals have been considered for millennia to have medicinal values. With the advent of modern medicine, many metal-based drugs have proven to be highly effective in the... (Review)
Review
Metals have been considered for millennia to have medicinal values. With the advent of modern medicine, many metal-based drugs have proven to be highly effective in the clinic. Many different metal ions have shown activity against a range of diseases. The unique electronic structure of transition metals offers great versatility, not always seen in organic drugs, in terms of the ability to tune the properties of a given molecule. This review gives a brief overview of the most established therapeutic metals, and their more common applications, such as platinum-based anticancer drugs. New developments within the field of metallodrugs and novel strategies being employed to improve methods of delivery, are also discussed.
Topics: Antineoplastic Agents; Biological Transport; Drug Delivery Systems; Drug Design; Humans; Organometallic Compounds; Organoplatinum Compounds; Photochemotherapy; Photosensitizing Agents; Platinum
PubMed: 24800466
DOI: 10.3184/003685014X13898980185076 -
Metal Ions in Life Sciences Feb 2018Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative... (Review)
Review
Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative stress production and toxicity. Over the last century, copper complexes have been developed as antimicrobials and for treating diseases involving copper dyshomeostasis (e.g., Wilson's disease). There now exists a repertoire of copper complexes that can regulate bodily copper through a myriad of mechanisms. Furthermore, many copper complexes are now being appraised for a variety of therapeutic indications (e.g., Alzheimer's disease and amyotrophic lateral sclerosis) that require a range of copper-related pharmacological affects. Cancer therapy is also drawing considerable attention since copper has been recognized as a limiting factor for multiple aspects of cancer progression including growth, angiogenesis, and metastasis. Consequently, 'old copper complexes' (e.g., tetrathiomolybdate and clioquinol) have been repurposed for cancer therapy and have demonstrated anticancer activity in vitro and in preclinical models. Likewise, new tailor-made copper complexes have been designed based on structural and biological features ideal for their anticancer activity. Human clinical trials continue to evaluate the therapeutic efficacy of copper complexes as anticancer agents and considerable progress has been made in understanding their pharmacological requirements. In this chapter, we present a historical perspective on the main copper complexes that are currently being repurposed for cancer therapy and detail several of the more recently developed compounds that have emerged as promising anticancer agents. We further provide an overview of the known mechanisms of action, including molecular targets and we discuss associated clinical trials.
Topics: Animals; Antineoplastic Agents; Coordination Complexes; Copper; Drug Design; Drug Repositioning; Humans; Molecular Structure; Neoplasms; Organometallic Compounds; Structure-Activity Relationship
PubMed: 29394035
DOI: 10.1515/9783110470734-022 -
Metal Ions in Life Sciences Feb 2018Anticancer platinum-based drugs are widely used in the treatment of a variety of tumorigenic diseases. They have been identified to target DNA and thereby induce... (Review)
Review
Anticancer platinum-based drugs are widely used in the treatment of a variety of tumorigenic diseases. They have been identified to target DNA and thereby induce apoptosis in cancer cells. Their reactivity to biomolecules other than DNA has often been associated with side effects that many cancer patients experience during chemotherapy. The development of metal compounds that target proteins rather than DNA has the potential to overcome or at least reduce the disadvantages of commonly used chemotherapeutics. Many exciting new metal complexes with novel modes of action have been reported and their anticancer activity was linked to selective protein interaction that may lead to improved accumulation in the tumor, higher selectivity and/or enhanced antiproliferative efficacy. The development of new lead structures requires bioanalytical methods to confirm the hypothesized modes of action or identify new, previously unexplored biological targets and pathways. We have selected original developments for review in this chapter and highlighted compounds on track toward clinical application.
Topics: Animals; Antineoplastic Agents; Binding Sites; Coordination Complexes; Drug Design; Humans; Models, Molecular; Molecular Targeted Therapy; Neoplasms; Organometallic Compounds; Protein Binding; Protein Conformation; Proteomics; Signal Transduction; Structure-Activity Relationship
PubMed: 29394032
DOI: 10.1515/9783110470734-019 -
Metal Ions in Life Sciences Feb 2018There has been much recent interest in the development of therapeutic transition metal-based complexes in part fueled by the clinical success of the platinum(II)... (Review)
Review
There has been much recent interest in the development of therapeutic transition metal-based complexes in part fueled by the clinical success of the platinum(II) anticancer drug, cisplatin. Yet known platinum drugs are limited by their high toxicity, severe side-effects, and incidences of drug resistance. Organometallic ruthenium-arene complexes have risen to prominence as a pharmacophore due to the success of other ruthenium drug candidates in clinical trials. In this chapter, we highlight higher order multinuclear ruthenium-arene complexes and their respective investigations as chemotherapeutic agents. We discuss their unique structural properties and the associated biochemical evaluation in the context of anticancer drug design. We also review the structural considerations for the design of these scaffolds and new therapeutic applications that are uncovered for this class of complexes.
Topics: Animals; Antineoplastic Agents; Coordination Complexes; Drug Design; Humans; Models, Molecular; Molecular Structure; Neoplasms; Organometallic Compounds; Protein Binding; Ruthenium Compounds; Structure-Activity Relationship
PubMed: 29394025
DOI: 10.1515/9783110470734-012 -
Metal Ions in Life Sciences Feb 2018Since ancient times gold and its complexes have been used as therapeutics against different diseases. In modern medicine gold drugs have been applied for the treatment... (Review)
Review
Since ancient times gold and its complexes have been used as therapeutics against different diseases. In modern medicine gold drugs have been applied for the treatment of rheumatoid arthritis, however, recently other medical applications have come into the focus of inorganic medicinal chemistry. This chapter provides a non-comprehensive overview of key developments in the field of gold anticancer drugs. Exciting findings on gold(I) and gold(III) complexes as antitumor agents are summarized together with a discussion of relevant aspects of their modes of action.
Topics: Animals; Antineoplastic Agents; Coordination Complexes; Drug Design; Gold Compounds; Humans; Models, Molecular; Molecular Structure; Neoplasms; Organometallic Compounds; Structure-Activity Relationship
PubMed: 29394026
DOI: 10.1515/9783110470734-013 -
Dalton Transactions (Cambridge, England... Feb 2016Cisplatin and other platinum compounds have had a huge impact in the treatment of cancers and are applied in the majority of anticancer chemotherapeutic regimens. The... (Review)
Review
Cisplatin and other platinum compounds have had a huge impact in the treatment of cancers and are applied in the majority of anticancer chemotherapeutic regimens. The success of these compounds has biased the approaches used to discover new metal-based anticancer drugs. In this perspective we highlight compounds that are apparently incompatible with the more classical (platinum-derived) concepts employed in the development of metal-based anticancer drugs, with respect to both compound design and the approaches used to validate their utility. Possible design approaches for the future are also suggested.
Topics: Antineoplastic Agents; Drug Design; Humans; Neoplasms; Organometallic Compounds; Transition Elements
PubMed: 26820398
DOI: 10.1039/c5dt03919c -
European Journal of Medicinal Chemistry Aug 2023Five new iron (II) complexes bearing imidazole-based (Imi-R) ligands with the general formula [Fe(η-CH)(CO)(PPh)(Imi-R)][CFSO] were synthesized and fully characterized...
Five new iron (II) complexes bearing imidazole-based (Imi-R) ligands with the general formula [Fe(η-CH)(CO)(PPh)(Imi-R)][CFSO] were synthesized and fully characterized by several spectroscopic and analytical techniques. All compounds crystallize in centrosymmetric space groups in a typical "piano stool" distribution. Given the growing importance of finding alternatives to overcome different forms of multidrug resistance, all compounds were tested against cancer cell lines with different ABCB1 efflux pump expression, namely, the doxorubicin-sensitive (Colo205) and doxorubicin-resistant (Colo320) human colon adenocarcinoma cell lines. Compound 3 bearing 1-benzylimidazole was the most active in both cell lines with IC values of 1.26 ± 0.11 and 2.21 ± 0.26 μM, respectively, being also slightly selective against the cancer cells (vs. MRC5 normal human embryonic fibroblast cell lines). This compound, together with compound 2 bearing 1H-1,3-benzodiazole, were found to display very potent ABCB1 inhibitory effect. Compound 3 also showed the ability to induce cell apoptosis. Iron cellular accumulation studies by ICP-MS and ICP-OES methods revealed that the compounds' cytotoxicity is not related to the extent of iron accumulation. Yet, it is worth mentioning that, from the compounds tested, 3 was the only one where iron accumulation was greater in the resistant cell line than in the sensitive one, validating the possible role of ABCB1 inhibition in its mechanism of action.
Topics: Humans; Iron; Adenocarcinoma; Colonic Neoplasms; Cell Line, Tumor; Organometallic Compounds; Doxorubicin; Ferrous Compounds; Drug Resistance, Neoplasm; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B
PubMed: 37187089
DOI: 10.1016/j.ejmech.2023.115466 -
Molecules (Basel, Switzerland) May 2021The synthesis of organometallic compounds with potential pharmacological activity has attracted the attention of many research groups, aiming to take advantage of... (Review)
Review
The synthesis of organometallic compounds with potential pharmacological activity has attracted the attention of many research groups, aiming to take advantage of aspects that the presence of the metal-carbon bond can bring to the design of new pharmaceutical drugs. In this context, we have gathered studies reported in the literature in which psychoactive benzodiazepine drugs were used as ligands in the preparation of organometallic and metal complexes and provide details on some of their biological effects. We also highlight that most commonly known benzodiazepine-based drugs display molecular features that allow the preparation of metallacycles via C-H activation. These organometallic compounds merit further attention regarding their potential biological effects, not only in terms of psychoactive drugs but also in the search for drug replacements, for example, for cancer treatments.
Topics: Benzodiazepines; Metals; Organometallic Compounds; Pharmaceutical Preparations
PubMed: 34068533
DOI: 10.3390/molecules26092796 -
Cancer Chemotherapy and Pharmacology May 2010Since the discovery of cis-platinum, many transition metal complexes have been synthesized and assayed for antineoplastic activity. In recent years, ruthenium-based... (Review)
Review
Since the discovery of cis-platinum, many transition metal complexes have been synthesized and assayed for antineoplastic activity. In recent years, ruthenium-based molecules have emerged as promising antitumor and antimetastatic agents with potential uses in platinum-resistant tumors or as alternatives to platinum. Ruthenium compounds theoretically possess unique biochemical features allowing them to accumulate preferentially in neoplastic tissues and to convert to their active state only after entering tumor cells. Intriguingly, some ruthenium agents show significant activity against cancer metastases but have minimal effects on primary tumors. Two ruthenium-based drugs, NAMI-A and KP1019, have reached human clinical testing. This review will highlight the chemical properties, mechanism of action, preclinical data, and early phase clinical results of these two lead ruthenium compounds. Other promising ruthenium agents will also be reviewed with emphasis on the novel ruthenium compound ONCO4417, and DW1/2 that has demonstrated Pim-1 kinase inhibition in preclinical systems. Further development of these and other ruthenium agents may rely on novel approaches including rational combination strategies as well as identification of potential pharmacodynamic biomarkers of drug activity aiding early phase clinical studies.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Dimethyl Sulfoxide; Drug Screening Assays, Antitumor; Drugs, Investigational; Humans; Indazoles; Neoplasm Metastasis; Organometallic Compounds; Ruthenium Compounds
PubMed: 20213076
DOI: 10.1007/s00280-010-1293-1