👤 Li RT.

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)₂bpy(4-CH₂OIBP-4'-CH₂OIBP)](PF₆) (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. In terms of protein expression, the expression of COX-2, MMP-9, NLRP3 and Caspase-1 proteins can be downregulated, indicating their ability to anti-inflammatory and overcome immune evasion. Furthermore, Ir-IBP-1 and Ir-IBP-2 can induce immunogenic cell death (ICD) by triggering the release of cell surface calreticulin (CRT), high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). Overall, iridium(III)-IBP conjugates exhibit various anti-tumor mechanisms, including mitochondrial damage, cell cycle arrest, inflammatory suppression, and induction of ICD. Show less

Title: Iridium(III) complexes conjugated with naproxen exhibit potent anti-tumor activities by inducing mitochondrial damage, modulating inflammation, and enhancing immunity. Abstract: A series of Ir(III)-naproxen (NPX) conjugates with the molecular formula [Ir(C^N)2bpy(4-CH2ONPX-4'-CH2ONPX)](PF6) (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. The main manifestations are a decrease in the mitochondrial membrane potential (MMP), an increase in reactive oxygen species (ROS) levels, and cell cycle arrest. Furthermore, Ir-NPX-1-3 could inhibit the migration and colony formation of cancer cells, demonstrating potential anti-metastatic ability. Finally, the anti-inflammatory and immunological applications of Ir-NPX-1-3 were verified. The downregulation of cyclooxygenase-2 (COX-2) and programmed death-ligand 1 (PD-L1) expression levels and the release of immunogenic cell death (ICD) related signaling molecules such as damage-associated molecular patterns (DAMPs) (cell surface calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP)) indicate that these Ir(III) -NPX conjugates are novel ICD inducers with synergistic effects in multiple anti-tumor pathways. Show less

Photoreactive Ru(II) complexes capable of ejecting ligands have been used extensively for photocaging applications and for the creation of "photocisplatin" reagents. The incorporation of distortion into the structure of the coordination complex lowers the energy of dissociative excited states, increasing the yield of the photosubstitution reaction. While steric clash between ligands induced by adding substituents at the coordinating face of the ligand has been extensively utilized, a lesser known, more subtle approach is to distort the coordination sphere by altering the chelate ring size. Here a systematic study was performed to alter metal-ligand bond lengths, angles, and to cause intraligand distortion by introducing a "linker" atom or group between two pyridine rings. The synthesis, photochemistry, and photobiology of five Ru(II) complexes containing CH₂, NH, O, and S-linked dipyridine ligands was investigated. All systems where stable in the dark, and three of the five were photochemically active in buffer. While a clear periodic trend was not observed, this study lays the foundation for the creation of photoactive systems utilizing an alternative type of distortion to facilitate photosubstitution reactions. Show less

Title: Lysosome-targeted cyclometalated iridium(III) complexes: JMJD inhibition, dual induction of apoptosis, and autophagy. Abstract: 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. And Ir-1-3 can block the cell cycle at the G2/M phase and inhibit cell migration and colony formation. Further studies show that Ir-1-3 can specifically accumulate in lysosomes, damage the integrity of lysosomes, and induce apoptosis and autophagy. Reduction of mitochondrial membrane potential and elevation of reactive oxygen species also contribute to the antitumor effects of Ir-1-3. Finally, Ir-1 can inhibit tumor growth effectively in vivo and increase the expression of H3K9Me3 in tumor tissues. Our study demonstrates that these iridium(III) complexes are promising anticancer agents with multiple functions, including the inhibition of JMJD and induction of apoptosis and autophagy. Show less

The β-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ²-O,O'-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ~ 30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ²-O,O'-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development. Show less

Six artesunate (ART) conjugated ruthenium(II) complexes (Ru(II)-ART conjugates) with the formula [Ru(N^N)₂bpy(4-CH₃-4'-CH₂OART)](PF₆)₂ (Ru-ART-1-3) and [Ru(N^N)₂bpy(4-CH₂OART-4'-CH₂OART)](PF₆)₂ (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. These two complexes can be effectively taken up by human cervical carcinoma (HeLa) cells. In addition, they selectively kill cancer cell lines while mildly affect normal cells. Mechanism studies have shown that HeLa cells treated with Ru-ART-3 and Ru-ART-6 show typical apoptotic characteristics (morphology changes, mitochondrial dysfunction, caspase cascade, etc.). On the other hand, the up regulation of Beclin-1 and conversion of LC3-I to LC3-II note the appearance of autophagy. As a result, Ru-ART-3 and Ru-ART-6 induce autophagy-dependent cell apoptosis via mitochondrial dysfunction and reactive oxygen species (ROS) accumulation. In this work, six artesunate (ART) conjugated ruthenium(II) complexes (Ru(II)-ART conjugates) have been synthesized and characterized. Among them, Ru-ART-3 and Ru-ART-6 exhibit better cytotoxicity. Mechanism studies have shown that HeLa cells treated with Ru-ART-3 and Ru-ART-6 show typical apoptotic characteristics (morphology changes, mitochondrial dysfunction, caspase cascade, etc.). On the other hand, the up regulation of Beclin-1 and conversion of LC3-I to LC3-II note the appearance of autophagy. Show less

Ruthenium(II) complexes developed for photodynamic therapy (PDT) are almost exclusively tris-bidentate systems with C₂ or D₃ symmetry. This is due to the fact that this structural framework commonly produces long-lived excited states, which, in turn, allow for the generation of large amounts of singlet oxygen (¹O₂) and other reactive oxygen species. Complexes containing tridentate ligands would be advantageous for biological applications as they are generally achiral (D_2d or C_2v symmetry), which eliminates the possibility of multiple isomers which could exhibit potentially different interactions with chiral biological entities. However, Ru(II) complexes containing tridentate ligands are rarely studied as candidates for photobiological applications, such as PDT, since they almost exclusively exhibit low quantum yields and very short excited-state lifetimes and, thus, are not capable of generating sufficient ¹O₂ or engaging in electron transfer reactions. Here, we report a proof-of-concept approach to make bis-tridentate Ru(II) complexes useful for PDT applications by altering their photophysical properties through the inclusion of N-heterocyclic carbene (NHC) ligands. Three NHC and two terpyridine ligands were studied to evaluate the effects of structural and photophysical modulations of bis-substituted Ru(II) complexes. The NHC complexes were found to have superior excited-state lifetimes, ¹O₂ production, and photocytotoxicity. To the best of our knowledge, these complexes are the most potent light-activated bis-tridentate complexes reported. Show less