Cyclometalated iridium(III)-lonidamine conjugates: Mitochondrial targeting and pyroptosis induction.

A series of cyclometalated Ir(III)-lonidamine (LND) complexes (Ir-LND-1-6) with the formula [Ir(C^N)bpy(4-CH-4'-CHOLND)](PF) (Ir-LND-1-3) and [Ir(C^N)bpy(4-CHOLND-4'-CHOLND)](PF) (Ir-LND-4-6) (C^N = 2-phenylpyridine (ppy, in Ir-LND-1 and Ir-LND-4), 2-(2-thienyl) pyridine (thpy, in Ir-LND-2 and Ir-LND-5) and 2-(2,4-difluorophenyl) pyridine (dfppy, in Ir-LND-3 and Ir-LND-6)), were designed and synthesized. 3-(4,5-dimethylthiazol-2-yl)-2,5-biphenyltetrazolium bromide (MTT) assay data showed that the cytotoxicity of Ir-LND-1-3 carry one LND moiety was superior to that of Ir-LND-4-6 with two LND moieties. Therefore, we selected Ir-LND-1-3 as model compounds to investigate the anti-tumor mechanism of the Ir(III)-LND system.

Design, synthesis, and antitumor mechanism investigation of iridium(III) complexes conjugated with ibuprofen.

The design and synthesis of a series of metal complexes formed by non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen (IBP) and iridium(III), with the molecular formula [Ir(C^N)bpy(4-CHOIBP-4'-CHOIBP)](PF) (Ir-IBP-1, Ir-IBP-2) (C^N = 2-phenylpyridine (ppy, Ir-IBP-1), 2-(2-thienyl)pyridine (thpy, Ir-IBP-2)) was introduced in this article. Firstly, it was found that the anti-proliferative activity of these complexes was more effective than that of cisplatin. Further research showed that Ir-IBP-1 and Ir-IBP-2 can accumulate in intracellular mitochondria, thereby disrupting mitochondrial membrane potential (MMP), increasing intracellular reactive oxygen species (ROS), blocking the G2/M phase of the cell cycle, and inducing cell apoptosis.

Iridium(III) complexes conjugated with naproxen exhibit potent anti-tumor activities by inducing mitochondrial damage, modulating inflammation, and enhancing immunity.

A series of Ir(III)-naproxen (NPX) conjugates with the molecular formula [Ir(C^N)bpy(4-CHONPX-4'-CHONPX)](PF) (Ir-NPX-1-3) were designed and synthesized, including C^N = 2-phenylpyridine (ppy, Ir-NPX-1), 2-(2-thienyl)pyridine (thpy, Ir-NPX-2) and 2-(2,4-difluorophenyl)pyridine (dfppy, Ir-NPX-3). Cytotoxicity tests showed that Ir-NPX-1-3 exhibited excellent antitumor activity, especially in A549R cells. The cellular uptake experiment showed that the complexes were mainly localized in mitochondria, and induced apoptosis in A549R cells by damaging the structure and function of mitochondria.

Antifungal activity of ruthenium (II) complex combined with fluconazole against drug-resistant Candida albicans in vitro and its anti-invasive infection in vivo.

With the abuse of antibiotics and azoles, drug-resistant Candida albicans infections have increased sharply and are spreading rapidly, thereby significantly reducing the antifungal efficacy of existing therapeutics. Several patients die of fungal infections every year. Therefore, there is an urgent requirement to develop new drugs.

Cyclometalated iridium(III) complexes combined with fluconazole: antifungal activity against resistant .

() is a ubiquitous clinical fungal pathogen. In recent years, combination therapy, a potential treatment method to overcome resistance, has gained traction. In this study, we synthesized a series of cyclometalated iridium(III) complexes with the formula [Ir(C-N)(tpphz)](PF) (C-N = 2-phenylpyridine (ppy, in ), 2-(2-thienyl)pyridine (thpy, in ), 2-(2,4-difluorophenyl) pyridine (dfppy, in ), tpphz = tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine) and polypyridyl ruthenium(II) complexes with the formula [Ru(N-N)(tpphz)](PF) (N-N = 2,2'-bipyridine (bpy, in ), 1,10-phenanthroline (phen, in ), 4,7-diphenyl-1,10-phenanthroline (DIP, in )), and investigated their antifungal activities against drug-resistant and their combination with fluconazole (FLC).

Heteronuclear Ru(II)-Re(I) complexes as potential photodynamic anticancer agents with anti-metastatic and anti-angiogenic activities.

Herein, three heterometallic Ru(II)-Re(I) complexes, [Ru(NN)(tpphz)Re(CO)Cl](PF) (N-N = 2,2'-bipyridine (bpy, in RuRe1), 1,10-phenanthroline (phen, in RuRe2), 4,7-diphenyl-1,10-phenanthroline (DIP, in RuRe3), tpphz = tetrapyrido[3,2-a:2',3'-c:3″,2″-h:2″',3″'-j]phenazine), using tpphz as a bridging ligand to connect Ru(II) polypyridyl moiety and Re(I) tricarbonyl moiety were designed and synthesized. Cytotoxicity tests revealed that RuRe1-3 exhibited high phototoxicities against several cancer cell lines tested, with IC values ranging from 0.8 to 6.

Lysosome-targeted cyclometalated iridium(III) complexes: JMJD inhibition, dual induction of apoptosis, and autophagy.

A series of cyclometalated iridium(III) complexes with the formula [Ir(C^N)2 L](PF6) (C^N = 2-phenylpyridine (ppy, in Ir-1), 2-(2-thienyl)pyridine (thpy, in Ir-2), 2-(2,4-difluorophenyl)pyridine (dfppy, in Ir-3), L = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol) were designed and synthesized, which utilize 8-hydroxyquinoline derivative as N^N ligands to chelate the cofactor Fe2+ of the Jumonji domain-containing protein (JMJD) histone demethylase. As expected, the results of UV/Vis titration analysis confirm the chelating capabilities of Ir-1-3 for Fe2+, and molecular docking studies also show that Ir-1-3 can interact with the active pocket of JMJD protein, and treatment of cells with Ir-1-3 results in significant upregulation of trimethylated histone 3 lysine 9 (H3K9Me3), indicating the inhibition of JMJD activity. Meanwhile, Ir-1-3 exhibit much higher cytotoxicity against the tested tumor cell lines compared with the clinical chemotherapeutic agent cisplatin.

8-Hydroxyquinoline-modified ruthenium(II) polypyridyl complexes for JMJD inhibition and photodynamic antitumor therapy.

As an ideal scaffold for metal ion chelation, 8-hydroxyquinoline (8HQ) can chelate different metal ions, such as Fe, Cu, Zn, Here, by integrating 8HQ with a ruthenium(II) polypyridyl moiety, two Ru(II)-8HQ complexes (Ru1 and Ru2), [Ru(N-N)L](PF) (L = 2-(1-imidazo[4,5-][1,10]phenanthrolin-2-yl)quinolin-8-ol; N-N: 2,2'-bipyridine (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2)) were designed and synthesized. In both complexes, ligand L is an 8HQ derivative designed to chelate the cofactor Fe of jumonji C domain-containing demethylase (JMJD). As expected, Ru1 and Ru2 could inhibit the activity of JMJD by chelating the key cofactor Fe of JMJD, resulting in the upregulation of histone-methylation levels in human lung cancer (A549) cells, and the upregulation was more pronounced under light conditions.

Jatavaleridoids A-H, eight new iridoids from the roots and rhizomes of Valeriana jatamansi Jones.

Eight new iridoids, jatavaleridoids A-H (1-8), were isolated from the roots and rhizomes of Valeriana jatamansi. Their structures and absolute configurations were elucidated based on NMR and HRESIMS spectroscopic data, as well as quantum chemical calculation. Structurally, compounds 1-5 and 8 were rare iridoids with long-chain fatty acid esters at C-10.

Synthesis, Characterization and Antitumor Mechanism Investigation of Heterometallic Ru(Ⅱ)-Re(Ⅰ) Complexes.

The development of heteronuclear metal complexes as potent anticancer agents has received increasing attention in recent years. In this study, two new heteronuclear Ru(Ⅱ)-Re(Ⅰ) metal complexes, [Ru(bpy)LRe(CO)(DIP)](PF) and [Ru(phen)LRe(CO)(DIP)](PF) [ and , L = 2-(4-pyridinyl)imidazolio[4,5-f][1,10]phenanthroline, bpy = 2,2'-bipyridine, DIP = 4,7-diphenyl-1,10-phenanthroline, phen = 1,10-phenanthroline], were synthesized and characterized. Cytotoxicity assay shows that and exhibit higher anticancer activity than cisplatin, and exist certain selectivity toward human cancer cells over normal cells.

Novel heterobimetallic Ir(III)-Re(I) complexes: design, synthesis and antitumor mechanism investigation.

The reasonable design of binuclear or multinuclear metal complexes has demonstrated their potential advantages in the anticancer field. Herein, three heterobimetallic Ir(III)-Re(I) complexes, [Ir(C^N)LRe(CO)DIP](PF) (C^N = 2-phenylpyridine (ppy, in IrRe-1), 2-(2-thienyl)pyridine (thpy, in IrRe-2) and 2-(2,4-difluorophenyl)pyridine (dfppy, in IrRe-3); L = pyridylimidazo[4,5-][1,10]phenanthroline; DIP = 4,7-diphenyl-1,10-phenanthroline), were designed and synthesized. The heterobimetallic IrRe-1-3 complexes show pH-sensitive emission properties, which can be used for specific imaging of lysosomes.

Selectively down-regulated PD-L1 by albumin-phenformin nanoparticles mediated mitochondrial dysfunction to stimulate tumor-specific immunological response for enhanced mild-temperature photothermal efficacy.

Background: Mild-temperature photothermal therapy (mild-PTT) has emerged as a highly promising antitumor strategy by triggering immunogenic cell death (ICD) to elicit both innate and adaptive immune responses for tumor control. However, mild-PTT still leads to the risk of tumor recurrence or metastasis because it could hardly completely eradicate tumors due to its impaired immunological efficacy owing to the enhanced PD-L1 expression in tumor cells after treatment.

Results: In this study, we described a hydrogen peroxide (HO) responsive manganese dioxide mineralized albumin nanocomposite loading with mitochondria function inhibitor phenformin (PM) and near-infrared photothermal dye indocyanine green (ICG) by modified two-step biomineralization method.

Synthesis, characterization and antitumor mechanism investigation of ruthenium(II) polypyridyl complexes with artesunate moiety.

Six artesunate (ART) conjugated ruthenium(II) complexes (Ru(II)-ART conjugates) with the formula [Ru(N^N)bpy(4-CH-4'-CHOART)](PF) (Ru-ART-1-3) and [Ru(N^N)bpy(4-CHOART-4'-CHOART)](PF) (Ru-ART-4-6) (N^N = 2,2'-bipyridine (bpy, in Ru-ART-1 and Ru-ART-4), 1,10-phenanthroline (phen, in Ru-ART-2 and Ru-ART-5) and 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru-ART-3 and Ru-ART-6)), were synthesized and characterized. Among them, Ru-ART-1-3 and Ru-ART-4-6 carry one and two ART moieties, respectively. Ru-ART-3 and Ru-ART-6 exhibit better cytotoxicity among six Ru(II)-ART conjugates.

Phosphorescent rhenium(I) complexes conjugated with artesunate: Mitochondrial targeting and apoptosis-ferroptosis dual induction.

Cell death is essential for cancer, which can be induced through multiple mechanisms. Ferroptosis, a newly emerging form of non-apoptotic cell death, involves the generation of iron-dependent reactive oxygen species (ROS). In this study, we designed and synthesized two artesunate (ART) conjugated phosphorescent rhenium(I) complexes (Re(I)-ART conjugates), [Re(N^N)(CO)(PyCHOART)](PF) (Re-ART-1 and Re-ART-2) (Py = pyridine, N^N = 1,10-phenanthroline (phen, in Re-ART-1) and 4,7-diphenyl-1,10-phenanthroline (DIP, in Re-ART-2)) that can specifically locate in the mitochondria of human cervical carcinoma (HeLa).

Zinc-Containing Metalloenzymes: Inhibition by Metal-Based Anticancer Agents.

DNA is considered to be the primary target of platinum-based anticancer drugs which have gained great success in clinics, but DNA-targeted anticancer drugs cause serious side-effects and easily acquired drug resistance. This has stimulated the search for novel therapeutic targets. In the past few years, substantial research has demonstrated that zinc-containing metalloenzymes play a vital role in the occurrence and development of cancer, and they have been identified as alternative targets for metal-based anticancer agents.

Mitochondria-targeted artesunate conjugated cyclometalated iridium(iii) complexes as potent anti-HepG2 hepatocellular carcinoma agents.

Hepatocellular carcinoma (HCC) poses a serious threat to people's health worldwide. Artesunate (ART), one of the classical antimalarial drugs, has recently been shown to exert significant cytotoxicity in various cancers, but its bioavailability is low. Cyclometalated iridium(iii) complexes have emerged as a promising class of anticancer therapeutic agents.

Copper-Catalyzed Decarboxylative Cycloaddition of Propiolic Acids, Azides, and Arylboronic Acids: Construction of Fully Substituted 1,2,3-Triazoles.

A copper-catalyzed decarboxylative cycloaddition of propiolic acids, azides, and arylboronic acids is described. The present reaction provides an efficient and convenient method for the synthesis of various fully substituted 1,2,3-triazoles from readily available starting materials. A possible mechanism is proposed.

Identification of two mitochondrial-targeting cyclometalated iridium(III) complexes as potent anti-glioma stem cells agents.

Glioma stem cells (GSCs) are thought to be responsible for the recurrence and invasion of glioblastoma multiform (GBM), which have been evaluated and exploited as the therapeutic target for GBM. Cyclometalated iridium(III) complexes have been demonstrated as the potential anticancer agents, however, their antitumor efficacies against GSCs are still unknown. Herein, we investigated the antitumor activity of two cyclometalated iridium(III) complexes [Ir(ppy)L](PF) (Ir1) and [Ir(thpy)L](PF) (Ir2) (ppy = 2-phenylpyridine, thpy = 2-(2-thienyl)pyridine and L = 4,4'-Bis(hydroxymethyl)-2,2'-bipyridine) against GSCs.

Valproic Acid-Functionalized Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents.

Valproic acid (VPA) is a short-chain, fatty acid type histone deacetylase inhibitor (HDACi), which can cause growth arrest and induce differentiation of transformed cells. Phosphorescent cyclometalated Ir complexes have emerged as potential anticancer agents. By conjugation of VPA to Ir complexes through an ester bond, VPA-functionalized cyclometalated iridium(III) complexes 1 a-3 a were designed and synthesized.

Ester-Modified Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents.

Organometallic iridium complexes are potent anticancer candidates which act through different mechanisms from cisplatin-based chemotherapy regimens. Here, ten phosphorescent cyclometalated iridium(III) complexes containing 2,2'-bipyridine-4,4'-dicarboxylic acid and its diester derivatives as ligands are designed and synthesized. The modification by ester group, which can be hydrolysed by esterase, facilitates the adjustment of drug-like properties.

Theranostic TEMPO-functionalized Ru(ii) complexes as photosensitizers and oxidative stress indicators.

New TEMPO-functionalized Ru(ii) polypyridyl complexes were synthesized as efficient theranostic photosensitizers for cancer treatment. Interestingly, due to the presence of a redox sensitive TEMPO moiety, an enhancement in the intracellular fluorescence of TEMPO-functionalized Ru(ii) complexes was observed during photodynamic treatment in both confocal microscopy and flow cytometry. This can be explained by the conversion of the TEMPO radical moiety to diamagnetic non-radical species in cells upon PDT-induced oxidative stress.

Tumor-targeted supramolecular nanoparticles self-assembled from a ruthenium-β-cyclodextrin complex and an adamantane-functionalized peptide.

We report here a supramolecular strategy to assemble a cyclodextrin-functionalized anticancer Ru(ii) complex with an adamantane-appended tumor-targeting peptide into discrete and stable phosphorescent nanostructures that can induce cell death in integrin αβ-rich tumor cells with high selectivity. This strategy presents new opportunities for the construction of tumor-targeting metallo-anticancer therapeutics.

Coumarin-appended phosphorescent cyclometalated iridium(iii) complexes as mitochondria-targeted theranostic anticancer agents.

Theranostic anticancer agents incorporating anticancer properties with capabilities for real-time treatment assessment are appealing candidates for chemotherapy. The design of mitochondria-targeted cytotoxic drugs represents a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, three coumarin-appended phosphorescent cyclometalated iridium(iii) complexes 1-3 have been explored as mitochondria-targeted theranostic anticancer agents.

Mono- and Dinuclear Phosphorescent Rhenium(I) Complexes: Impact of Subcellular Localization on Anticancer Mechanisms.

Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes (Re1 and Re2), along with their corresponding dinuclear complexes (Re3 and Re4), were designed and synthesized as potent anticancer agents.

Cyclometalated iridium(iii) complexes as lysosome-targeted photodynamic anticancer and real-time tracking agents.

Stimuli-activatable photosensitizers (PSs) are highly desirable for photodynamic therapy (PDT) to selectively demolish tumor cells. On the other hand, lysosomes are emerging as attractive anticancer targets. Herein, four cyclometalated iridium(iii)-β-carboline complexes with pH-responsive singlet oxygen (O) production and lysosome-specific imaging properties have been designed and synthesized.