Heme-copper oxidases (HCOs) are terminal enzymes on the mitochondrial or bacterial respiratory electron transport chain, which utilize a unique heterobinuclear active site to catalyze the 4H
/4e
...reduction of dioxygen to water. This process involves a proton-coupled electron transfer (PCET) from a tyrosine (phenolic) residue and additional redox events coupled to transmembrane proton pumping and ATP synthesis. Given that HCOs are large, complex, membrane-bound enzymes, bioinspired synthetic model chemistry is a promising approach to better understand heme-Cu-mediated dioxygen reduction, including the details of proton and electron movements. This review encompasses important aspects of heme-O
and copper-O
(bio)chemistries as they relate to the design and interpretation of small molecule model systems and provides perspectives from fundamental coordination chemistry, which can be applied to the understanding of HCO activity. We focus on recent advancements from studies of heme-Cu models, evaluating experimental and computational results, which highlight important fundamental structure-function relationships. Finally, we provide an outlook for future potential contributions from synthetic inorganic chemistry and discuss their implications with relevance to biological O
-reduction.
Metallodrugs in cancer nanomedicine Peña, Quim; Wang, Alec; Zaremba, Orysia ...
Chemical Society reviews,
04/2022, Letnik:
51, Številka:
7
Journal Article
Recenzirano
Metal complexes are extensively used for cancer therapy. The multiple variables available for tuning (metal, ligand, and metal-ligand interaction) offer unique opportunities for drug design, and have ...led to a vast portfolio of metallodrugs that can display a higher diversity of functions and mechanisms of action with respect to pure organic structures. Clinically approved metallodrugs, such as cisplatin, carboplatin and oxaliplatin, are used to treat many types of cancer and play prominent roles in combination regimens, including with immunotherapy. However, metallodrugs generally suffer from poor pharmacokinetics, low levels of target site accumulation, metal-mediated off-target reactivity and development of drug resistance, which can all limit their efficacy and clinical translation. Nanomedicine has arisen as a powerful tool to help overcome these shortcomings. Several nanoformulations have already significantly improved the efficacy and reduced the toxicity of (chemo-)therapeutic drugs, including some promising metallodrug-containing nanomedicines currently in clinical trials. In this critical review, we analyse the opportunities and clinical challenges of metallodrugs, and we assess the advantages and limitations of metallodrug delivery, both from a nanocarrier and from a metal-nano interaction perspective. We describe the latest and most relevant nanomedicine formulations developed for metal complexes, and we discuss how the rational combination of coordination chemistry with nanomedicine technology can assist in promoting the clinical translation of metallodrugs.
Metallodrugs offer potential for unique mechanism of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. This ...review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. Examples of metal compounds and chelating agents currently in clinical use, clinical trials or preclinical development are highlighted.
This review gives an overview of the relevant medicinal chemistry of platinum, palladium, gold and ruthenium complexes, which could be used for anticancer or biomedical applications. Display omitted
•Pt complexes that intercalate with DNA typically exhibit anticancer activity.•Pd complexes showed good binding affinity to DNA and proteins.•The thiol–enzymes are considered key molecular targets of anticancer Au complexes.•Ru complexes has been considered to be an attractive alternative to Pt complexes.
Light-emitting supramolecular coordination complexes (SCCs) have been widely studied for applications in the chemical and biological sciences. Herein, we report the coordination-driven self-assembly ...of two highly emissive platinum(II) supramolecular triangles (1 and 2) containing BODIPY-based bridging ligands. The metallacycles exhibit favorable anticancer activities against HeLa cells (IC
of 6.41 and 2.11 μM). The characteristic ∼570 nm fluorescence of the boron dipyrromethene (BODIPY) moieties in the metallacycles permits their intracellular visualization using confocal microscopy. Additionally, the BODIPY fluorophore is an excellent photodynamic agent, making the metallacycles as ideal therapeutics for photodynamic therapy (PDT) and chemotherapy. In vitro studies demonstrate that the combination indexes against HeLa cells are 0.56 and 0.48 for 1 and 2, respectively, confirming their synergistic anticancer effect. More importantly, these SCCs also exhibit superior anticancer efficacy toward cisplatin-resistant A2780cis cell line by combining PDT and chemotherapy, showing promise in overcoming drug resistance. This study exploits a multicomponent approach to self-assembled metallacages that enables design of effective theranostic agents wherein the platinum acceptors are toxic chemotherapeutics and the BODIPY donors are imaging probes and photosensitizers. Since each piece may be independently tuned, i.e., Pt(II) polypyridyl fragment swapped for Pt(II) phosphine, the activity may be optimized without a total redesign of the system.
The discovery of cisplatin's antitumor activity in 1969 prompted the search for novel metal-containing complexes as potential anticancer drugs. Among these novel complexes, metal N-heterocyclic ...carbene (NHC) complexes have recently gained considerable attention because they perfectly fit prerequisites for efficient drug design and fast optimization. Moreover, most of them have shown higher cytotoxicity than cisplatin. This review describes the advances that have been achieved in using transition metal (Ag, Au, Pt, Pd, Cu, Ni, and Ru) complexes containing NHC ligands as antitumor agents. Their modes of action at the cellular lever are further discussed. All these initial achievements clearly demonstrate the great potential of metal-NHC complexes as antitumor agents.
In addition to the already described ligand
, two pyclen-based lanthanide chelators,
and
, bearing two specific picolinate two-photon antennas (tailor-made for each targeted metal) and one acetate ...arm arranged in a dissymmetrical manner, have been synthesized, to form a complete family of lanthanide luminescent bioprobes: Eu
, Sm
, Yb
, Tb
, and Dy
. Additionally, the symmetrically arranged regioisomer
was also synthesized as well as its Eu
complex to highlight the astonishing positive impact of the dissymmetrical
-distribution of the functional chelating arms. The investigation clearly shows the high performance of each bioprobe, which, depending on the complexed lanthanide, could be used in various applications. Each presents high brightness, quantum yields, and lifetimes. Staining of the complexes into living human breast cancer cells was observed. In addition,
two-photon microscopy was performed for the first time on a living zebrafish model with Eu
. No apparent toxicity was detected on the growth of the zebrafish, and images of high quality were obtained.
The paper compiles a single case study on the national EU integration coordination in Georgia since 1991 to date. The paper aims to ground Georgia’s case in the existing academic literature with a ...detailed case description and testing of the EU integration coordination mechanisms in Georgia based on theories and models in the PA literature. Georgia’s coordination mechanisms are assessed against external incentives, such as ‘socialisation’ v. ‘conditionality’ (Schimmelfennig, 2009), and classified in terms of Kassim’s (2003) system of national coordination. The paper describes five distinct periods in the evolution of EU integration coordination formats: the first encounter (1991-1999); the silhouettes of coordination (1999-2004); the deliberate coordination (2004-2014); the pragmatic coordination (2014-2022) and the coordination limbo (2022 to date). EU integration coordination structures from 2004 to 2014 are likened to a comprehensive centraliser - with the centre being the driving force of the entire coordination process, with all the issues or thematic areas being depicted in respective planning documents. Since 2014, the country’s approach has been compared to that of a selective centraliser, since Georgia shows signs of selectiveness in its ambitions to deliver on a nationally agreed EU policy outcome. The paper finds that, unlike prevalent patterns in EU integration coordination, the relative stagnation of the EU coordination process happens after the accession; in Georgia, this has occurred during the onset of the conditionality stage, which makes this an outlier case. In assessing the reasons for the weakening of the process of coordination, this case supports findings that the actor-centric approach is vital to explaining the coordination efforts (Dimitrova & Toshkov, 2007; Fink-Hafner, 2013). The paper concludes that a significant improvement of existing EU integration coordination structures is needed to build a comprehensive approach, reinforced with horizontal coordination and networking, to construct an agreed and inclusive EU integration coordination.
The success of platinum-based anticancer agents has motivated the exploration of novel metal-based drugs for several decades, whereas problems such as drug-resistance and systemic toxicity hampered ...their clinical applications and efficacy. Stimuli-responsiveness of some metal complexes offers a good opportunity for designing site-specific prodrugs to maximize the therapeutic efficacy and minimize the side effect of metallodrugs. This review presents a comprehensive and up-to-date overview on the therapeutic stimuli-responsive metallodrugs that have appeared in the past two decades, where stimuli such as redox, pH, enzyme, light, temperature, and so forth were involved. The compounds are classified into three major categories based on the nature of stimuli, that is, endo-stimuli-responsive metallodrugs, exo-stimuli-responsive metallodrugs, and dual-stimuli-responsive metallodrugs. Representative examples of each type are discussed in terms of structure, response mechanism, and potential medical applications. In the end, future opportunities and challenges in this field are tentatively proposed. With diverse metal complexes being introduced, the foci of this review are pointed to platinum and ruthenium complexes.
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