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Current Opinion in Chemical Biology Apr 2023Metal-based anticancer agents occupy a distinct chemical space due to their particular coordination geometry and reactivity. Despite the initial DNA-targeting paradigm... (Review)
Review
Metal-based anticancer agents occupy a distinct chemical space due to their particular coordination geometry and reactivity. Despite the initial DNA-targeting paradigm for this class of compounds, it is now clear that they can also be tuned to target proteins in cells, depending on the metal and ligand scaffold. Since metallodrug discovery is dominated by phenotypic screenings, tailored proteomics strategies were crucial to identify and validate protein targets of several investigative and clinically advanced metal-based drugs. Here, such experimental approaches are discussed, which showed that metallodrugs based on ruthenium, gold, rhenium and even platinum, can selectively and specifically target proteins with clear-cut down-stream effects. Target identification strategies are expected to support significantly the mechanism-driven clinical translation of metal-based drugs.
Topics: Antineoplastic Agents; Platinum; Ruthenium; Gold; DNA; Coordination Complexes
PubMed: 36599256
DOI: 10.1016/j.cbpa.2022.102257 -
Journal of the American Chemical Society May 2019The manipulation and modulation of biomolecules has the potential to herald new modes of Biology and Medicine through chemical "editing". Key to the success of such... (Review)
Review
The manipulation and modulation of biomolecules has the potential to herald new modes of Biology and Medicine through chemical "editing". Key to the success of such processes will be the selectivities, reactivities and efficiencies that may be brought to bear in bond-formation and bond-cleavage in a benign manner. In this Perspective, we use select examples, primarily from our own research, to examine the current opportunities, limitations and the particular potential of metal-mediated processes as exemplars of possible alternative catalytic modes and manifolds to those already found in nature.
Topics: Alkynes; Azides; Catalysis; Copper; Palladium; Proteins; Ruthenium
PubMed: 30974939
DOI: 10.1021/jacs.8b13187 -
Photochemistry and Photobiology Jan 2022We report new ruthenium complexes bearing the lipophilic bathophenanthroline (BPhen) ligand and dihydroxybipyridine (dhbp) ligands which differ in the placement of the...
We report new ruthenium complexes bearing the lipophilic bathophenanthroline (BPhen) ligand and dihydroxybipyridine (dhbp) ligands which differ in the placement of the OH groups ([(BPhen) Ru(n,n'-dhbp)]Cl with n = 6 and 4 in 1 and 2 , respectively). Full characterization data are reported for 1 and 2 and single crystal X-ray diffraction for 1 . Both 1 and 2 are diprotic acids. We have studied 1 , 1 , 2 , and 2 (B = deprotonated forms) by UV-vis spectroscopy and 1 photodissociates, but 2 is light stable. Luminescence studies reveal that the basic forms have lower energy MLCT states relative to the acidic forms. Complexes 1 and 2 produce singlet oxygen with quantum yields of 0.05 and 0.68, respectively, in acetonitrile. Complexes 1 and 2 are both photocytotoxic toward breast cancer cells, with complex 2 showing EC light values as low as 0.50 μM with PI values as high as >200 vs. MCF7. Computational studies were used to predict the energies of the MLCT and MC states. An inaccessible MC state for 2 suggests a rationale for why photodissociation does not occur with the 4,4'-dhbp ligand. Low dark toxicity combined with an accessible MLCT state for O generation explains the excellent photocytotoxicity of 2.
Topics: Breast Neoplasms; Female; Humans; Ligands; Phenanthrolines; Ruthenium; Ruthenium Compounds
PubMed: 34411308
DOI: 10.1111/php.13508 -
Nature Communications Aug 2021As a basic structure of most polypyridinal metal complexes, [Ru(bpy)], has the advantages of simple structure, facile synthesis and high yield, which has great potential...
As a basic structure of most polypyridinal metal complexes, [Ru(bpy)], has the advantages of simple structure, facile synthesis and high yield, which has great potential for scientific research and application. However, sonodynamic therapy (SDT) performance of [Ru(bpy)] has not been investigated so far. SDT can overcome the tissue-penetration and phototoxicity problems compared to photodynamic therapy. Here, we report that [Ru(bpy)] is a highly potent sonosensitizer and sonocatalyst for sonotherapy in vitro and in vivo. [Ru(bpy)] can produce singlet oxygen (O) and sono-oxidize endogenous 1,4-dihydronicotinamide adenine dinucleotide (NADH) under ultrasound (US) stimulation in cancer cells. Furthermore, [Ru(bpy)] enables effective destruction of mice tumors, and the therapeutic effect can reach deep tissues over 10 cm under US irradiation. This work paves a way for polypyridinal metal complexes to be applied to the noninvasive precise sonotherapy of cancer.
Topics: Animals; Antineoplastic Agents; Humans; Mice; Mice, Inbred BALB C; NAD; Neoplasms; Oxidation-Reduction; Porphyrins; Ruthenium; Singlet Oxygen; Ultrasonic Therapy; Ultrasonic Waves
PubMed: 34408151
DOI: 10.1038/s41467-021-25303-1 -
Nature Communications May 2018The viability of building artificial metabolic pathways within a cell will depend on our ability to design biocompatible and orthogonal catalysts capable of achieving...
The viability of building artificial metabolic pathways within a cell will depend on our ability to design biocompatible and orthogonal catalysts capable of achieving non-natural transformations. In this context, transition metal complexes offer unique possibilities to develop catalytic reactions that do not occur in nature. However, translating the potential of metal catalysts to living cells poses numerous challenges associated to their biocompatibility, and their stability and reactivity in crowded aqueous environments. Here we report a gold-mediated C-C bond formation that occurs in complex aqueous habitats, and demonstrate that the reaction can be translated to living mammalian cells. Key to the success of the process is the use of designed, water-activatable gold chloride complexes. Moreover, we demonstrate the viability of achieving the gold-promoted process in parallel with a ruthenium-mediated reaction, inside living cells, and in a bioorthogonal and mutually orthogonal manner.
Topics: Catalysis; Cells; Coordination Complexes; Gold; HeLa Cells; Humans; Ruthenium
PubMed: 29765051
DOI: 10.1038/s41467-018-04314-5 -
International Journal of Molecular... Apr 2022(1) Background: Ruthenium and osmium complexes attract increasing interest as next generation anticancer drugs. Focusing on structure-activity-relationships of this...
(1) Background: Ruthenium and osmium complexes attract increasing interest as next generation anticancer drugs. Focusing on structure-activity-relationships of this class of compounds, we report on 17 different ruthenium(II) complexes and four promising osmium(II) analogues with cinnamic acid derivatives as O,S bidentate ligands. The aim of this study was to determine the anticancer activity and the ability to evade platin resistance mechanisms for these compounds. (2) Methods: Structural characterizations and stability determinations have been carried out with standard techniques, including NMR spectroscopy and X-ray crystallography. All complexes and single ligands have been tested for cytotoxic activity on two ovarian cancer cell lines (A2780, SKOV3) and their cisplatin-resistant isogenic cell cultures, a lung carcinoma cell line (A549) as well as selected compounds on three non-cancerous cell cultures in vitro. FACS analyses and histone γH2AX staining were carried out for cell cycle distribution and cell death or DNA damage analyses, respectively. (3) Results: IC50 values show promising results, specifically a high cancer selective cytotoxicity and evasion of resistance mechanisms for Ru(II) and Os(II) compounds. Histone γH2AX foci and FACS experiments validated the high cytotoxicity but revealed diminished DNA damage-inducing activity and an absence of cell cycle disturbance thus pointing to another mode of action. (4) Conclusion: Ru(II) and Os(II) compounds with O,S-bidentate ligands show high cytotoxicity without strong effects on DNA damage and cell cycle, and this seems to be the basis to circumvent resistance mechanisms and for the high cancer cell specificity.
Topics: Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cisplatin; Coordination Complexes; Drug Resistance, Neoplasm; Female; Histones; Humans; Ligands; Molecular Structure; Organometallic Compounds; Osmium; Ovarian Neoplasms; Ruthenium
PubMed: 35563367
DOI: 10.3390/ijms23094976 -
Drug Design, Development and Therapy 2020Platinum (Pt)-based anticancer drugs such as cisplatin have been used to treat various cancers. However, they have some limitations including poor selectivity and... (Review)
Review
Platinum (Pt)-based anticancer drugs such as cisplatin have been used to treat various cancers. However, they have some limitations including poor selectivity and toxicity towards normal cells and increasing chemoresistance. Therefore, there is a need for novel metallo-anticancers, which has not been met for decades. Since the initial introduction of ruthenium (Ru) polypyridyl complex, a number of attempts at structural evolution have been conducted to improve efficacy. Among them, half-sandwich Ru-arene complexes have been the most prominent as an anticancer platform. Such complexes have clearly shown superior anticancer profiles such as increased selectivity toward cancer cells and ameliorating toxicity against normal cells compared to existing Pt-based anticancers. Currently, several Ru complexes are under human clinical trials. For improvement in selectivity and toxicity associated with chemotherapy, Ru complexes as photodynamic therapy (PDT), and photoactivated chemotherapy (PACT), which can selectively activate prodrug moieties in a specific region, have also been investigated. With all these studies on these interesting entities, new metallo-anticancer drugs to at least partially replace existing Pt-based anticancers are anticipated. This review covers a brief description of Ru-based anticancer complexes and perspectives.
Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Coordination Complexes; Drug Screening Assays, Antitumor; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents; Ruthenium
PubMed: 33299303
DOI: 10.2147/DDDT.S275007 -
Biosensors Sep 2022Two-dimensional (2D) layered materials functionalized with monometallic or bimetallic dopants are excellent materials to fabricate clinically useful biosensors. Herein,...
Two-dimensional (2D) layered materials functionalized with monometallic or bimetallic dopants are excellent materials to fabricate clinically useful biosensors. Herein, we report the synthesis of ruthenium nanoparticles (RuNPs) and nickel molybdate nanorods (NiMoO NRs) functionalized porous graphitic carbon nitrides (PCN) for the fabrication of sensitive and selective biosensors for cardiac troponin I (cTn-I). A wet chemical synthesis route was designed to synthesize PCN-RuNPs and PCN-NiMoO NRs. Morphological, elemental, spectroscopic, and electrochemical investigations confirmed the successful formation of these materials. PCN-RuNPs and PCN-NiMoO NRs interfaces showed significantly enhanced electrochemically active surface areas, abundant sites for immobilizing bioreceptors, porosity, and excellent aptamer capturing capacity. Both PCN-RuNPs and PCN-NiMoO NRs materials were used to develop cTn-I sensitive biosensors, which showed a working range of 0.1-10,000 ng/mL and LODs of 70.0 pg/mL and 50.0 pg/mL, respectively. In addition, the biosensors were highly selective and practically applicable. The functionalized 2D PCN materials are thus potential candidates to develop biosensors for detecting acute myocardial infractions.
Topics: Biosensing Techniques; Electrochemical Techniques; Graphite; Nickel; Porosity; Ruthenium; Troponin I
PubMed: 36290921
DOI: 10.3390/bios12100783 -
International Journal of Molecular... Dec 2022Cancer is one of the leading cause of lethality worldwide, CRC being the third most common cancer reported worldwide, with 1.85 million cases and 850,000 deaths...
Cancer is one of the leading cause of lethality worldwide, CRC being the third most common cancer reported worldwide, with 1.85 million cases and 850,000 deaths annually. As in all other cancers, kinases are one of the major enzymes that play an essential role in the incidence and progression of CRC. Thus, using multi-kinase inhibitors is one of the therapeutic strategies used to counter advanced-stage CRC. Regorafenib is an FDA-approved drug in the third-line therapy of refractory metastatic colorectal cancer. Acquired resistance to cancers and higher toxicity of these drugs are disadvantages to the patients. To counter this, combination therapy is used as a strategy where a minimal dose of drugs can be used to get a higher efficacy and reduce drug resistance development. Ruthenium-based compounds are observed to be a potential alternative to platinum-based drugs due to their significant safety and effectiveness. Formerly, our lab reported Ru-1, a ruthenium-based compound, for its anticancer activity against multiple cancer cells, such as HepG2, HCT116, and MCF7. This study evaluates Ru-1's activity against regorafenib-resistant HCT116 cells and as a combination therapeutic with regorafenib. Meanwhile, the mechanism of the effect of Ru-1 alone and with regorafenib as a combination is still unknown. In this study, we tested a drug combination (Ru-1 and regorafenib) against a panel of HT29, HCT116, and regorafenib-resistant HCT116 cells. The combination showed a synergistic inhibitory activity. Several mechanisms underlying these numerous synergistic activities, such as anti-proliferative efficacy, indicated that the combination exhibited potent cytotoxicity and enhanced apoptosis induction. Disruption of mitochondrial membrane potential increased intracellular ROS levels and decreased migratory cell properties were observed. The combination exhibited its activity by regulating PI3K/Akt and p38 MAP kinase signalling. This indicates that the combination of REG/Ru-1 targets cancer cells by modulating the PI3K/Akt and ERK signalling.
Topics: Humans; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Ruthenium; Apoptosis; Colorectal Neoplasms; Phenylurea Compounds; Cell Line, Tumor
PubMed: 36614133
DOI: 10.3390/ijms24010686 -
Molecules (Basel, Switzerland) Jul 2021Lung cancer is one of the most common malignancies with the highest mortality rate and the second-highest incidence rate after breast cancer, posing a serious threat to... (Review)
Review
Lung cancer is one of the most common malignancies with the highest mortality rate and the second-highest incidence rate after breast cancer, posing a serious threat to human health. The accidental discovery of the antitumor properties of cisplatin in the early 1960s aroused a growing interest in metal-based compounds for cancer treatment. However, the clinical application of cisplatin is limited by serious side effects and drug resistance. Therefore, other transition metal complexes have been developed for the treatment of different malignant cancers. Among them, Ru(II/III)-based complexes have emerged as promising anticancer drug candidates due to their potential anticancer properties and selective cytotoxic activity. In this review, we summarized the latest developments of Ru(II/III) complexes against lung cancer, focusing mainly on the mechanisms of their biological activities, including induction of apoptosis, necroptosis, autophagy, cell cycle arrest, inhibition of cell proliferation, and invasion and metastasis of lung cancer cells.
Topics: Animals; Antineoplastic Agents; Coordination Complexes; Cytotoxins; Humans; Lung Neoplasms; Ruthenium
PubMed: 34361543
DOI: 10.3390/molecules26154389