Binding Mechanisms and Therapeutic Activity of Heterocyclic Substituted Arylazothioformamide Ligands and Their Cu(I) Coordination Complexes
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SUBMITTER: Tiwari L
PROVIDER: S-EPMC11375723 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
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Project description:The synthesis, photophysics, and photobiological activities of a series of novel neutral heteroleptic cyclometalated iridium(iii) complexes incorporating boron dipyrromethene (BODIPY) substituted N-heterocyclic carbene (NHC) ligands (Ir1-Ir5) are reported. The effect of the substitution position of BODIPY on the NHC ligands, either on C4 of the phenyl ring (Ir1-Ir3) or C5 of the benzimidazole unit (Ir4 and Ir5), and its linker type (single or triple bond) on the photophysical properties was studied. Ir1-Ir5 exhibited BODIPY-localized intense 1IL (intraligand transition)/1MLCT (metal-to-ligand charge transfer) absorption at 530-543 nm and 1,3IL/1,3CT (charge transfer) emission at 582-610 nm. The nanosecond transient absorption results revealed that the lowest triplet excited states of these complexes were the BODIPY-localized 3?,?* states. Complexes Ir4 and Ir5 exhibited blue-shifted 1IL absorption and 1,3IL/1,3CT emission bands compared to the corresponding absorption and emission bands in complexes Ir1 and Ir3. However, replacing the methyl substituents on N3 of benzimidazole in complexes Ir1 and Ir4 with oligoether substituents in Ir3 and Ir5, respectively, did not impact the energies of the low-energy absorption and emission bands in the corresponding complexes. Water-soluble complexes Ir3 and Ir5 have been explored as photosensitizers for in vitro photodynamic therapy (PDT) effects toward human SKMEL28 melanoma cells. Ir3 showed no dark cytotoxicity (EC50 > 300 ?M) but good photocytotoxic activity (9.66 ± 0.28 ?M), whereas Ir5 exhibited a higher dark cytotoxicity (20.2 ± 1.26 ?M) and excellent photocytotoxicity (0.15 ± 0.01 ?M). The phototherapeutic indices with visible light (400-700 nm) activation were >31 for Ir3 and 135 for Ir5. Ir3 and Ir5 displayed 1O2 quantum yields of 38% and 22% in CH3CN, respectively, upon 450 nm excitation. Ir5 was more effective at generating reactive oxygen species (ROS) in vitro. Ir5 was also active against Staphylococcus aureus upon visible light activation, with a phototherapeutic index of >15 and EC50 value of 6.67 ?M. These photobiological activities demonstrated that these neutral Ir(iii) complexes are promising in vitro PDT reagents, and substitution at C5 on the benzimidazole group of the NHC ligand was superior to C4 substitution on the phenyl ring.
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Project description:With the class of shock-absorbing proteins, nature created some of the most robust materials combining both mechanical strength and elasticity. Their excellent ability to dissipate energy to prevent surrounding cells from damage is an interesting property that regularly is exploited for applications in biomimetic materials. Similar to biomaterials, where mechanical stimuli are transmitted into a (bio)chemical response, mechanophoric catalysts transform mechanical energy into a chemical reaction. Force transmission is realized commonly by polymeric handles directing the applied force to the mechanophoric bond, which in turn leads to stress-induced activation of the catalyst. Therefore, shock-absorbing proteins able to take up and store mechanical energy elastically for subsequent force transduction to the labile bond seem to be perfect candidates to fulfill this task. Here, we report on the synthesis of two different latent mechanophoric copper(I) bis(N-heterocyclic carbene) complexes bearing either two carboxyl groups or two amino groups which allow conjugation reactions with either the N- or the C-terminus of amino acids or peptides. The chosen catalysts can be activated, for instance, by applying external mechanical force via ultrasound, removing one N-heterocyclic carbene (NHC) ligand. Post-modification of the mechanophoric catalysts via peptide coupling (Gly, Val) and first reactions showed that the mechanoresponsive behavior was still present after the coupling. Subsequent polycondensation of both catalysts lead to a polyamide including the Cu(I) moiety. Mechanochemical activation by ultrasound showed conversions in the copper(I)-catalyzed alkyne-azide "click" reaction (CuAAC) up to 9.9% proving the potential application for the time and spatial controlled CuAAC.
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Project description:A series of heteroleptic three-coordinate Cu(i) complexes bearing monodentate N-heterocyclic carbene (NHC) ligands of the type 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene (SIPr), and bidentate N-donor ligands of the type unsymmetrically-substituted dimethyl dipyridylamine (Me2Hdpa) and bis(mesityl)biazanaphthenequinone (mesBIAN) have been synthesized. The complexes [Cu(IPr)(3,4'-Me2Hdpa)]PF6, 1; [Cu(IPr)(3,5'-Me2Hdpa)]PF6, 2; [Cu(IPr)(3,6'-Me2Hdpa)]PF6, 3; [Cu(IPr)(mesBIAN)]PF6, 6; [Cu(SIPr)(3,4'-Me2Hdpa)]PF6, 7; [Cu(SIPr)(3,5'-Me2Hdpa)]PF6, 8; and [Cu(SIPr)(3,3'-Me2Hdpa)]PF6, 11 have been characterized by 1H and 13C NMR spectroscopies, elemental analysis, cyclic voltammetry, and photophysical studies in solid and solution phase. Single crystal X-ray structures were obtained for all complexes except 11. The crystallographic data reveal a mononuclear structure for all complexes with the copper atom ligated by one C and two N atoms. The UV-Vis absorption spectra of all dipyridylamine complexes in CH2Cl2 show a strong ligand-centered absorption band around 250 nm and a strong metal-to-ligand charge transfer (MLCT) band around 300 nm. When irradiated with UV light, the complexes exhibit strong emission maxima at 453-482 nm with photoluminescence quantum yields (PLQY) ranging from 0.21 to 0.87 in solid state. While the PLQY values are comparable to those of the symmetrical [Cu(IPr)(Me2Hdpa)]PF6 complexes, a stabilizing CH-π interaction has been reduced in the current systems. In particular, complex 3 lacks any strong CH-π interaction, but emits more efficiently than 1 and 2 wherein the interactions exist. Structural data analysis was performed to clarify the role of ligands' plane angle and the NH/CH⋯F interactions to the observed light interaction of unsymmetrical [Cu(NHC)(Me2Hdpa)]PF6 complexes. DFT calculations were performed to assist in the assignment of the electronic structure and excited state behavior of the complexes.
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Project description:Luminescent Cu(I) complexes are promising emitting materials for electroluminescent devices due to their low cost and abundant resources, as well as high emission efficiency. It is well-known that N-heterocyclic carbenes (NHCs) are excellent ligands for transition metal complexes. To investigate the photophysical properties of Cu(I)-NHC complexes, a series of new mononuclear four-coordinate Cu(I) complexes supported by the diphosphine ligand bis[2-(diphenylphosphino)phenyl]ether (POP) and the NHC ligands, consisting of imidazolylidene and pyrimidine units, were synthesized and fully characterized. To tune the photophysical properties of these Cu(I)-NHC complexes, the NHC ligands were attached with electron-withdrawing/donating groups (fluorine, chlorine, methyl and methoxyl) at the pyrimidine unit. All of these Cu(I)-NHC complexes adopt the typical distorted tetrahedral configuration. The electron-donating groups can lead to shorter Cu-N bond distances and longer Cu-C bond distances compared to the electron-withdrawing groups. Theoretical calculation results show that the highest occupied molecular orbitals are mainly distributed on the Cu(I) ion, POP, and carbene unit, while the lowest unoccupied molecular orbitals are mostly located on the pyrimidine unit of NHC ligands. The lowest energy electronic transitions of these Cu(I)-NHC complexes are mainly the metal-to-ligand charge transfer transition and ligand-to-ligand charge transfer transition. These Cu(I)-NHC complexes in solid state show tunable emissions from 530 to 618 nm with efficiencies of 0.5-38.1% at room temperature. The photophysical behaviors of these complexes at 298 and 50 K match well with the thermally activated delayed fluorescence (TADF) characteristics.
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Project description:A series of methylpalladium(II) complexes with pyrimidine-NHC ligands carrying different aryl- and alkyl substituents R ([((pym)^(NHC-R))Pd(II)(CH3)X] with X = Cl, CF3COO, CH3) has been prepared by transmetalation reactions from the corresponding silver complexes and chloro(methyl)(cyclooctadiene)palladium(II). The dimethyl(1-(2-pyrimidyl)-3-(2,6-diisopropylphenyl)imidazolin-2-ylidene)palladium(II) complex was synthesized via the free carbene route. All complexes were fully characterized by standard methods and in three cases also by a solid state structure.
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Project description:The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure-activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR.
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Project description:A series of coinage metal complexes asymmetrically substituted 2,5-diaryl phosphole ligands is reported. Structure, identity, and purity of all obtained complexes were corroborated with state-of-the-art techniques (multinuclear NMR, mass spectrometry, elemental analysis, X-ray diffraction) in solution and solid state. All complexes obtained feature luminescence in solution as well as in the solid state. Additionally, DOSY-MW NMR estimation experiments were performed to achieve information about the aggregation behavior of the complexes in solution allowing a direct comparison with their structures observed in the solid state.
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Project description:Rare mono- and diorganopentaphosphido cobalt complexes are accessible by P-P condensation using the unprecedented, reactive cobalt-gallium tetraphosphido complex [K(dme)2{(MesBIAN)Co(μ-η4:η2-P4)Ga(nacnac)}] (2). Compound 2 was prepared in good yield by reaction of [K(Et2O){(MesBIAN)Co(η4-1,5-cod)}] [1, BIAN = bis(mesitylimino)acenaphthene diimine, cod = 1,5-cyclooctadiene] with [Ga(nacnac)(η2-P4)] (nacnac = CH[CMeN(2,6-iPr2C6H3)]2). Reactions with R2PCl (R = iPr, tBu, and Cy) selectively afford [(MesBIAN)Co(cyclo-P5R2)] (3a-c), which feature η4-coordinated 1,1-diorganopentaphosphido ligands. The mechanism of formation of these species has been studied by 31P{1H} NMR spectroscopy and DFT calculations. In the case of 3a (R = iPr), it was possible to identify the intermediate [(MesBIAN)Co(μ-η4:η2-P5iPr2)Ga(nacnac)] (4) by single-crystal X-ray diffraction. A related, monosubstituted organopentaphosphido cobalt complex [(MesBIAN)Co(μ-η4:η1-P5 tBu)GaCl(nacnac)] (5) was isolated by reacting dichloroalkylphosphane tBuPCl2 with 2. Heterobimetallic complexes such as 2 thus may enable the targeted construction of a range of new metal-coordinated polyphosphorus frameworks by P-P condensation.
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Project description:Unraveling the function of biological copper (Cu) requires tools that can selectively recognize and manipulate this trace nutrient within the complex chemical environment of biological systems. Increasing evidence suggests that cells maintain an exchangeable pool of Cu(I) that is buffered in the high zeptomolar to low attomolar range. While mixed amine-thioether donors have been commonly employed for the design of Cu(I)-selective ligands and probes, their dissociation constants are limited to the pico- to femtomolar range. To address this challenge, we combined our previously devised phosphine sulfide-stabilized phosphine donor motifs with a rigid 1,2-phenylene or 1,8-naphthylene ligand backbone. The resulting ligands, phenPS and naphPS, bind Cu(I) with a 1:1 complex stoichiometry and offer dissociation constants of 0.6 and 0.8 zM, respectively. Concluding from the crystal structures of the free and Cu(I)-bound ligands, the 1,2-phenylene-bridged ligand phenPS provides a high degree of structural preorganization to accommodate the Cu(I) center without large conformational changes, while the 1,8-naphthylene-bridged ligand revealed significant out-of-plane distortions in both the free and Cu(I)-bound states. Both ligands were accessed by palladium-catalyzed cross-coupling reactions from the corresponding arylhalides under mild conditions, an approach that could be readily expanded toward the design of other ligands and probes.
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