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1.
J Med Chem ; 67(17): 14912-14926, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39226239

RESUMEN

Given the extensive role of lipids in cancer development, there is substantial clinical interest in developing therapies that target lipid metabolism. In this study, we identified one cyclometalated iridium complex (Ir2) that exhibits potent antiproliferation activity in MIA PaCa-2 cells by regulating fatty acid metabolism and sphingolipid metabolism simultaneously. Ir2 also efficiently overcomes cisplatin resistance in vitro. Satisfyingly, the generated Ir2@F127 carriers, as a temperature-sensitive in situ gelling system of Ir2, showed effective cancer treatment with minimal side effects in an in vivo xenograft study. To the best of our knowledge, Ir2 is the first reported cyclometalated iridium complex that exerts anticancer activity in MIA PaCa-2 cells by intervening in lipid metabolism, which provides an alternative pathway for the anticancer mechanism of cyclometalated iridium complexes.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Ácidos Grasos , Iridio , Esfingolípidos , Humanos , Iridio/química , Iridio/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Ácidos Grasos/metabolismo , Ácidos Grasos/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Línea Celular Tumoral , Esfingolípidos/metabolismo , Ratones , Oxidación-Reducción , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Reprogramación Metabólica
2.
J Med Chem ; 67(18): 16157-16164, 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39231957

RESUMEN

Photodynamic therapy delivers more targeted cell killing than classical chemotherapy. It uses light-absorbing compounds, photosensitizers (PSs), to generate lethal reactive oxygen species (ROS) at sites of localized irradiation. Transition metal complexes are attractive PSs due to their photostability, visible-light absorption, and high ROS yields. Here, we introduce a low-molecular weight, photostable iridium complex, [Ir(thpy)2(benz)]Cl, 1, that localizes to the Golgi apparatus, mitochondria, and endoplasmic reticulum, absorbs visible light, phosphoresces strongly, generates 1O2 with 43% yield, and undergoes cellular elimination after 24 h. 1 shows low dark toxicity and under remarkably low doses (3 min, 20-30 mJ s-1 cm-2) of 405 or 455 nm light, it causes killing of bladder (EJ), malignant melanoma (A375), and oropharyngeal (OPSCC72) cancer cells, with high phototoxic indices > 100-378. 1 is also an efficient PS in 3D melanoma spheroids, with repeated short-time irradiation causing cumulative killing.


Asunto(s)
Complejos de Coordinación , Iridio , Luz , Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Iridio/química , Iridio/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/efectos de la radiación , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Especies Reactivas de Oxígeno/metabolismo
3.
J Med Chem ; 67(18): 16235-16247, 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39250558

RESUMEN

Triggering ferroptosis represents a promising anticancer therapeutic strategy, but the development of a selective ferroptosis inducer for cancer-specific therapy remains a great challenge. Herein, a H2S-responsive iridium(III) complex NA-Ir has been well-designed as a ferroptosis inducer. NA-Ir could selectively light up H2S-rich cancer cells, primarily localize in mitochondria, intercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage, exhibiting higher anticancer activity under light irradiation. Mechanistic studies showed that NA-Ir-mediated PDT triggered lipid peroxidation and glutathione peroxidase 4 downregulation through ROS production and GSH depletion, resulting in ferroptosis through multiple pathways. Moreover, the intense mtDNA damage can activate the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway, leading to ferritinophagy and further ferroptosis. RNA-sequencing analysis showed that NA-Ir-mediated PDT mainly affects the expression of genes related to ferroptosis, autophagy, and cancer immunity. This study demonstrates the first cancer-specific example with ferroptosis and cGAS-STING activation, which provides a new strategy for multimodal synergistic therapy.


Asunto(s)
Ferroptosis , Iridio , Proteínas de la Membrana , Nucleotidiltransferasas , Ferroptosis/efectos de los fármacos , Humanos , Iridio/química , Iridio/farmacología , Nucleotidiltransferasas/metabolismo , Proteínas de la Membrana/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Línea Celular Tumoral , Ratones , ADN Mitocondrial/metabolismo , Especies Reactivas de Oxígeno/metabolismo
4.
J Med Chem ; 67(18): 16195-16208, 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39264254

RESUMEN

In this paper, three new iridium(III) complexes: [Ir(piq)2(DFIPP)]PF6 (piq = deprotonated 1-phenylisoquinoline, DFIPP = 3,4-difluoro-2-(1H-imidazo[4,5-f][1,10]phenenthrolin-2-yl)phenol, 3a), [Ir(bzq)2(DFIPP)]PF6 (bzq = deprotonated benzo[h]quinoline, 3b), and [Ir(ppy)2(DFIPP)]PF6 (ppy = deprotonated 1-phenylpyridine, 3c), were synthesized and characterized. The complexes were found to be nontoxic to tumor cells via 3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide (MTT) assay. Surprisingly, its liposome-entrapped complexes 3alip, 3blip, and 3clip on B16 cells showed strong cytotoxicity (IC50 = 13.6 ± 2.8, 9.6 ± 1.1, and 18.9 ± 2.1 µM). Entry of 3alip, 3blip, and 3clip into B16 cells decreases mitochondrial membrane potential, regulates Bcl-2 family proteins, releases cytochrome c, triggers caspase family cascade reaction, and induces apoptosis. In addition, we also found that 3alip, 3blip, and 3clip triggered ferroptosis and autophagy. In vivo studies demonstrated that 3blip inhibited melanoma growth in C57 mice with a high inhibitory rate of 83.95%, and no organic damage was found in C57 mice.


Asunto(s)
Antineoplásicos , Apoptosis , Complejos de Coordinación , Iridio , Liposomas , Iridio/química , Iridio/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ratones , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Ratones Endogámicos C57BL , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Melanoma Experimental/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos
5.
Dalton Trans ; 53(36): 15176-15189, 2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39221457

RESUMEN

Cyclometalated iridium(III) compounds have been widely explored due to their outstanding photo-physical properties and multiple anticancer activities. In this paper, three cyclometalated iridium(III) compounds [Ir(ppy)2(DBDIP)]PF6 (5a), [Ir(bzq)2(DBDIP)]PF6 (5b), and [Ir(piq)2(DBDIP)]PF6 (5c) (ppy: 2-phenylpyridine; bzq: benzo[h]quinoline; piq: 1-phenylisoquinoline, and DBDIP: 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and the mechanism of antitumor activity was investigated. Compounds photoactivated by visible light show strong cytotoxicity against tumor cells, especially toward A549 cells. Biological experiments such as migration, cellular localization, mitochondrial membrane potential and permeability, reactive oxygen species (ROS) and calcium ion level detection were performed, and they demonstrated that the compounds induced the apoptosis of A549 cells through a mitochondrial pathway. At the same time, oxidative stress caused by ROS production increases the release of damage-related molecules and the expression of porogen gasdermin D (GSDMD), and the content of LDH released from damaged cell membranes also increased. Besides, the content of the lipid peroxidation product, malondialdehyde (MDA), increased and the expression of GPX4 decreased. These indicate that the compounds promote cell death by combining ferroptosis and pyroptosis. The results reveal that cyclometalated iridium(III) compounds 5a-5c may be a potential chemotherapeutic agent for photodynamic therapy of cancers.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Ensayos de Selección de Medicamentos Antitumorales , Iridio , Especies Reactivas de Oxígeno , Humanos , Iridio/química , Iridio/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Células A549 , Apoptosis/efectos de los fármacos , Luz , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Estructura Molecular , Calcio/metabolismo , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Procesos Fotoquímicos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química
6.
J Am Chem Soc ; 146(37): 25589-25599, 2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39248725

RESUMEN

Cross-linking strategies have found wide applications in chemical biology, enabling the labeling of biomolecules and monitoring of protein-protein interactions. Nitrone exhibits remarkable versatility and applicability in bioorthogonal labeling due to its high reactivity with strained alkynes via the strain-promoted alkyne-nitrone cycloaddition (SPANC) reaction. In this work, four cyclometalated iridium(III) polypyridine complexes functionalized with two nitrone units were designed as novel phosphorogenic bioorthogonal reagents for bioimaging and phototherapeutics. The complexes showed efficient emission quenching, which is attributed to an efficient nonradiative decay pathway via the low-lying T1/S0 minimum energy crossing point (MECP), as revealed by computational studies. However, the complexes displayed significant emission enhancement and lifetime extension upon reaction with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) derivatives. In particular, they showed a remarkably higher reaction rate toward a bis-cyclooctyne derivative (bis-BCN) compared with its monomeric counterpart (mono-BCN). Live-cell imaging and (photo)cytotoxicity studies revealed higher photocytotoxicity in bis-BCN-pretreated cells, which is ascribed to the enhanced singlet oxygen (1O2) photosensitization resulting from the elimination of the nitrone-associated quenching pathway. Importantly, the cross-linking properties and enhanced reactivity of the complexes make them highly promising candidates for the development of hydrogels and stapled/cyclized peptides, offering intriguing photophysical, photochemical, and biological properties. Notably, a nanosized hydrogel (2-gel) demonstrated potential as a drug delivery system, while a stapled peptide (2-bis-pDIKK) exhibited p53-Mdm2 inhibitory activity related to apoptosis and a cyclized peptide (2-bis-RGD) showed cancer selectivity.


Asunto(s)
Complejos de Coordinación , Iridio , Óxidos de Nitrógeno , Iridio/química , Óxidos de Nitrógeno/química , Óxidos de Nitrógeno/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Humanos , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Nanomedicina Teranóstica
7.
Biochemistry ; 63(17): 2111-2130, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39140188

RESUMEN

In previous work, we reported on iridium(III) (Ir(III)) complex-peptide hybrids as amphiphilic conjugates (IPH-ACs) and triptycene-peptide hybrids as amphiphilic conjugates (TPH-ACs) and found that these hybrid compounds containing three cationic KK(K)GG peptide units through C6-C8 alkyl linkers induce paraptosis II, which is one of the nonapoptotic programmed cell death (PCD) types in Jurkat cells and different from previously reported paraptosis. The details of that study revealed that the paraptosis II induced by IPH-ACs (and TPH-ACs) proceeds via a membrane fusion or tethering of the endoplasmic reticulum (ER) and mitochondria, and Ca2+ transfer from the ER to mitochondria, which results in a loss of mitochondrial membrane potential (ΔΨm) in Jurkat cells. However, the detailed mechanistic studies of paraptosis II have been conducted only in Jurkat cells. In the present work, we decided to conduct mechanistic studies of paraptosis II in HeLa-S3 and A549 cells as well as in Jurkat cells to study the general mechanism of paraptosis II. Simultaneously, we designed and synthesized new TPH-ACs functionalized with peptides that contain cyclohexylalanine, which had been reported to enhance the localization of peptides to mitochondria. We found that TPH-ACs containing cyclohexylalanine promote paraptosis II processes in Jurkat, HeLa-S3 and A549 cells. The results of the experiments using fluorescence Ca2+ probes in mitochondria and cytosol, fluorescence staining agents of mitochondria and the ER, and inhibitors of paraptosis II suggest that TPH-ACs induce Ca2+ increase in mitochondria and the membrane fusion between the ER and mitochondria almost simultaneously, suggesting that our previous hypothesis on the mechanism of paraptosis II should be revised.


Asunto(s)
Mitocondrias , Humanos , Células Jurkat , Células HeLa , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/metabolismo , Calcio/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Antracenos/química , Antracenos/farmacología , Células A549 , Iridio/química , Iridio/farmacología , Muerte Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Paraptosis
8.
Dalton Trans ; 53(34): 14258-14264, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39129539

RESUMEN

The aggregation of amyloid ß (Aß) peptides is a significant hallmark of Alzheimer's disease (AD), and the detection of Aß aggregates and the inhibition of their formation are important for the diagnosis and treatment of AD, respectively. Herein, we report a series of benzothiazole-based Ir(III) complexes HN-1 to HN-8 that exhibit appreciable inhibition of Aß aggregation in vitro and in living cells. These Ir(III) complexes can induce a significant fluorescence increase when binding to Aß fibrils and Aß oligomers, while their measured log D values suggest these compounds could have enhanced blood-brain barrier (BBB) permeability. In vivo studies show that HN-1, HN-2, HN-3, and HN-8 successfully penetrate the BBB and stain the amyloid plaques in AD mouse brains after a 10-day treatment, suggesting that these Ir(III) complexes could act as lead compounds for AD therapeutic and diagnostic agent development.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Benzotiazoles , Complejos de Coordinación , Iridio , Agregado de Proteínas , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Iridio/química , Iridio/farmacología , Animales , Ratones , Benzotiazoles/química , Benzotiazoles/farmacología , Humanos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico , Agregado de Proteínas/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Tiazoles
9.
Chemosphere ; 364: 143034, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39117083

RESUMEN

Bisphenol S (BPS) is a common pollutant in the environment and has posed a potential threat to aquatic animals and human health. To accurately assess the pollution level and ecological risk of BPS, there is an urgent need to establish simple and sensitive detection methods for BPS. In this study, BPS complete antigen was successfully prepared by introducing methyl 4-bromobutyrate and coupling bovine serum albumin (BSA). The monoclonal antibody against BPS (anti-BPS mAb) with high affinity (1: 256,000) was developed based on the BPS complete antigen, which showed low cross-reactivity with BPS structural analogues. Then, an electrochemical immunosensor was constructed to detect BPS using multi-walled carbon nanotubes and gold nanoflower composites as signal amplification elements and using anti-BPS mAb as the probe. The electrochemical immunosensor had a linear range from 1 to 250 ng⋅mL-1 and a limit of detection (LOD) down to 0.6 ng⋅mL-1. Additionally, a more stable and sensitive lateral flow immunoassay (LFIA) for BPS was developed based on iridium oxide nanoparticles, with a visual detection limit of 1 ng⋅mL-1, which was 10 times lower than that of classical Au-NPs LFIA. After evaluation of their stability and specificity, the reliability of these two methods were further validated by measuring BPS concentrations in the water and fish tissues. Thus, this study provides sensitive, robust and rapid methods for the detection of BPS in the environment and organisms, which can provide a methodological reference for monitoring environmental contaminants.


Asunto(s)
Técnicas Electroquímicas , Iridio , Límite de Detección , Fenoles , Sulfonas , Inmunoensayo/métodos , Fenoles/análisis , Fenoles/química , Iridio/química , Técnicas Electroquímicas/métodos , Sulfonas/química , Sulfonas/análisis , Oro/química , Nanopartículas del Metal/química , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Animales , Técnicas Biosensibles/métodos , Contaminantes Químicos del Agua/análisis , Nanotubos de Carbono/química , Nanopartículas/química
10.
Bioorg Med Chem ; 112: 117842, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39173538

RESUMEN

The decline of antibiotics efficacy worldwide has recently reached a critical point urging for the development of new strategies to regain upper hand on multidrug resistant bacterial strains. In this context, the raise of photodynamic therapy (PDT), initially based on organic photosensitizers (PS) and more recently on organometallic PS, offers promising perspectives. Many PS exert their biological effects through the generation of reactive oxygen species (ROS) able to freely diffuse into and to kill surrounding bacteria. Hijacking of the bacterial iron-uptake systems with siderophore-PS conjugates would specifically target pathogens. Here, we report the synthesis of unprecedented conjugates between the siderophore desferrioxamine B (DFOB) and an antibacterial iridium(III) PS. Redox properties of the new conjugates have been determined at excited states and compared to that of an antibacterial iridium PS previously reported by our groups. Tested on nosocomial pathogen Pseudomonas aeruginosa and other bacteria, these conjugates demonstrated significant inhibitory activity when activated with blue LED light. Ir(III) conjugate and iridium free DFOB-2,2'-dipyridylamine ligands were crystallized in complex with FoxA, the outer membrane transporter involved in DFOB uptake in P. aeruginosa and revealed details of the binding mode of these unprecedented conjugates.


Asunto(s)
Antibacterianos , Complejos de Coordinación , Deferoxamina , Iridio , Luz , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa , Sideróforos , Iridio/química , Iridio/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Deferoxamina/farmacología , Deferoxamina/química , Deferoxamina/síntesis química , Sideróforos/química , Sideróforos/farmacología , Sideróforos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Pseudomonas aeruginosa/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Relación Dosis-Respuesta a Droga
11.
J Inorg Biochem ; 261: 112706, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39197384

RESUMEN

In this study, the ligand EIPP (5-ethoxy-2-(1H-imidazo[4,5-f] [1,10] phenanthrolin-2-yl)phenol) and [Ir(ppy)2(EIPP)](PF6)] (5a, ppy = 2-phenylpyridine) and [Ir(piq)2(EIPP)](PF6)] (5b, piq = 1-phenylisoquinoline) were synthesized and they were entrapped into liposomes to produce 5alipo and 5blipo. 5a and 5b were characterized via HRMS, NMR, UV-vis and IR. The cytotoxicity of 5a, 5b, 5alipo and 5blipo on cancer and non-cancer cells was estimated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). MTT assay demonstrated that 5a and 5b did not show any significant cellular activity but their liposome-encapsulated 5alipo and 5blipo had significant toxic effects. The mechanism of 5alipo, 5blipo-inducing apoptosis was explored by studying cellular uptake, mitochondrial localization, mitochondrial membrane potential, cytochrome C, glutathione (GSH), malondialdehyde (MDA) and protein immunoblotting. The results demonstrated that 5alipo and 5blipo caused a release of cytochrome C, downregulated the expression of Bcl-2, upregulated the expression of BAX, activated caspase 3, and downregulated PARP expression. It was shown that 5alipo and 5blipo could inhibit cancer cell proliferation in G2/M phase by regulating p53 and p21 proteins. Additionally, 5alipo and 5blipo induced autophagy through an adjustment from LC3-I to LC3-II and caused ferroptosis. The in vivo antitumor activity of 5alipo was examined in detail.


Asunto(s)
Antineoplásicos , Apoptosis , Complejos de Coordinación , Iridio , Liposomas , Humanos , Iridio/química , Iridio/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Animales , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos
12.
Biosensors (Basel) ; 14(8)2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39194598

RESUMEN

As a commonly used metal ion, iron(II) (Fe2+) ions pose a potential threat to ecosystems and human health. Therefore, it is particularly important to develop analytical techniques for the rapid and accurate detection of Fe2+ ions. However, the development of near-infrared (NIR) luminescence probes with good photostability for Fe2+ ions remain challenging. In this work, we report a novel iridium(III) complex-based luminescence probe for the sensitive and rapid detection of Fe2+ ions in a solution based on an Fe2+-mediated reduction reaction. This probe is capable of sensitively detecting Fe2+ ions with a limit of detection (LOD) of 0.26 µM. Furthermore, this probe shows high photostability, and its luminescence remains stable under 365 nm irradiation over a time period of 30 min. To our knowledge, this is first iridium(III) complex-based NIR probe for the detection of Fe2+ ions. We believe that this work provides a new method for the detection of Fe2+ ions and has great potential for future applications in water quality testing and human monitoring.


Asunto(s)
Iridio , Hierro , Límite de Detección , Iridio/química , Hierro/química , Hierro/análisis , Iones , Humanos , Complejos de Coordinación/química , Espectroscopía Infrarroja Corta , Técnicas Biosensibles
13.
Bioorg Chem ; 151: 107706, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39128244

RESUMEN

New iridium(III) compounds (C1-C3) bearing 2-(1H-benzimidazol-2-yl)quinoline ligands with different side groups (benzyl, 2,3,4,5,6-pentamethylbenzyl and 2,3,4,5,6-pentafluorobenzyl) were synthesized and characterized by using spectroscopic analyses. The effects of different side groups of iridium compounds on the photophysical and electrochemical properties have been investigated. The cytotoxicity and apoptosis of the compounds have been evaluated on breast cancer cell lines using various methods including MTT assay, flow cytometry, qRT-PCR, and colony formation. The cytotoxicity of C1, expressed as IC50 values, was found to be 11.76 µM for MDA-MB-231 and 5.35 µM for MCF-7 cells. For C3, the IC50 value was 16.22 µM for MDA-MB-231 and 8.85 µM for MCF-7 cells. In both cell lines, increased levels of Bax and caspase 3, along with downregulation of BCL-2 and positive annexin V staining, were observed, confirming apoptosis. Moreover, the colony-forming abilities in both cell lines decreased after C1 and C3 complex treatment. All these results suggest that the compounds C1 and C3 may have potential in the treatment of breast cancer, though further research is needed to confirm their efficacy.


Asunto(s)
Antineoplásicos , Apoptosis , Complejos de Coordinación , Ensayos de Selección de Medicamentos Antitumorales , Iridio , Quinolinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Relación Dosis-Respuesta a Droga , Técnicas Electroquímicas , Iridio/química , Iridio/farmacología , Estructura Molecular , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Relación Estructura-Actividad , Compuestos de Bencilo/síntesis química , Compuestos de Bencilo/química , Compuestos de Bencilo/farmacología
14.
Dalton Trans ; 53(34): 14438-14450, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39143927

RESUMEN

In this paper, we present the synthesis of four new complexes: the dimeric precursor [Ir(dmppz)2(µ-Cl)]2 (1) (Hdmppz - 3,5-dimethyl-1-phenyl-1H-pyrazole) and heteroleptic bis-cyclometalated complexes: [Ir(dmppz)2(Py2CO)]PF6·½CH2Cl2 (2), [Ir(dmppz)2(H2biim)]PF6·H2O (3), and [Ir(dmppz)2(PyBIm)]PF6 (4), with auxiliary N,N-donor ligands: 2-di(pyridyl)ketone (Py2CO), 2,2'-biimidazole (H2biim) and 2-(2'-pyridyl)benzimidazole (PyBIm). In the obtained complexes, SC-X-ray analysis revealed that Ir(III) has an octahedral coordination sphere with chromophores of the type {IrN2C2Cl2} (1) or {IrN4C2} (2-4). The complexes obtained, which have been fully characterised by physicochemical methods (CHN, TG, FTIR, UV-Vis, PL and 1H, 13C, 15N NMR), were used to continue our studies on the factors influencing the cytotoxic properties of potential chemotherapeutic agents (in vitro). To this end, the following studies are presented: (i) comparative analysis of the effects on the biological properties of N,N-donor ligands and C,N-donor ligands in the studied complexes, (ii) studies of the interactions of the compounds with the selected molecular target: DNA and BSA (UV-Vis, CD and PL methods), (iii) and the reactivity towards redox molecules: GSH, NADH (UV-Vis and/or ESI-MS methods), (iv) cytotoxic activity (IC50) of potential chemotherapeutics against MCF-7, K-562 and CCRF-CEM cell lines.


Asunto(s)
Antineoplásicos , Proliferación Celular , Complejos de Coordinación , Iridio , Pirazoles , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Humanos , Ligandos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Iridio/química , Iridio/farmacología , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Teoría Cuántica , ADN/química , ADN/metabolismo , Estructura Molecular , Modelos Moleculares , Procesos Fotoquímicos
16.
Front Biosci (Landmark Ed) ; 29(8): 304, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39206916

RESUMEN

BACKGROUND: The six Platinum group metal elements (PGEs) comprising Ruthenium, Rhodium, Palladium, Platinum, Iridium and Osmium are grouped together in the periodic table. Human activities are mostly responsible for releasing PGEs into the environment. This systematic review focused on three PGEs with the greatest anthropogenic use, including in vehicle catalytic converters: Platinum (Pt), Palladium (Pd), and Rhodium (Rh). Consequently, these represent the greatest contributors to environmental pollution. The current review of in vivo toxicological studies (mammalian models) and in vitro cell exposure studies examined the potential harmful effects of these metalloids to mammalians, and their possible toxicity to human health. METHODS: We applied Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology to conduct a comprehensive search and evaluation of records in the available literature published between 01/01/2009 and 01/15/2024 in four databases. PROSPERO code ID: CRD42024471558. Results concerning the health effects of PGEs were extracted from articles according to the inclusion and exclusion criteria. After screening the records for eligibility, 22 studies were included in the final analysis. RESULTS: This systematic review revealed that airborne PGEs significantly increased the activation of pathologic pathways in several human organs and/or perturbed various metabolic pathways. In view of the known pro-inflammatory and organ-degenerative effects of PGEs, the paucity of studies on the effect of PGEs on the central nervous system and on possible correlations with neurodegenerative diseases were particularly evident. CONCLUSIONS: The clinical complexity and chronic nature of PGE-related pathologies indicate that targeted research is essential. In light of the increasing incidence of non-communicable diseases, particular attention should be paid to the design of epidemiological studies and to environmental monitoring services.


Asunto(s)
Platino (Metal) , Humanos , Animales , Platino (Metal)/toxicidad , Rodio/toxicidad , Iridio/toxicidad , Iridio/química , Paladio/toxicidad , Rutenio/química
17.
Inorg Chem ; 63(35): 16404-16417, 2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39150967

RESUMEN

The limited optical penetration depth and hypoxic tumor microenvironment (TME) are key factors that hinder the practical applications of conventional photodynamic therapy (PDT). To fundamentally address these issues, self-luminescent photosensitizers (PSs) can achieve efficient PDT. Herein, a self-chemiluminescence (CL)-triggered Ir complex PS, namely, IrL2, with low-O2-dependence type I photochemical processes is reported for efficient PDT. The rational design achieves efficient chemiluminescence resonance energy transfer (CRET) from covalently bonded luminol units to the Ir complex in IrL2 under the catalysis of H2O2 and hemoglobin (Hb) to generate O2•- and 1O2. Liposome IrL2H nanoparticles (NPs) are constructed by loading IrL2 and Hb. The intracellular H2O2 and loaded Hb catalyze the luminol part of IrL2H, and the Ir2 part is then excited to produce types I and II reactive oxygen species (ROS) through CRET, inducing cell death, even under hypoxic conditions, and promoting cell apoptosis. IrL2H is used for tumor imaging and inhibits tumor growth in 4T1-bearing mouse models through intratumoral injection without external light sources. This work provides new designs for transition metal complex PSs that conquer the limitations of external light sources and the hypoxic TME in PDT.


Asunto(s)
Iridio , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Animales , Iridio/química , Iridio/farmacología , Ratones , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Luminiscencia , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Hipoxia Tumoral/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Estructura Molecular
18.
Sci Rep ; 14(1): 18443, 2024 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-39117886

RESUMEN

Hypoxia is an important feature of the tumor microenvironment (TME) of most solid tumors, and it is closely linked to cancer cell proliferation, therapy resistance, and the tumor immune response. Herein, we describe a method for hypoxia-induced heterogeneous oxygen distribution in xenograft tumors based on phosphorescence imaging microscopy (PLIM) using intravascular and intracellular oxygen probes. We synthesized Ir(III) complexes with polyethylene glycol (PEG) units of different molecular weights into the ligand as intravascular oxygen probes, BTP-PEGm (m = 2000, 5000, 10000, 20000). BTP-PEGm showed red emission with relatively high emission quantum yield and high oxygen sensitivity in saline. Cellular and in vivo experiments using these complexes revealed that BTP-PEG10000 was the most suitable probe in terms of blood retention and ease of intravenous administration in mice. PLIM measurements of xenograft tumors in mice treated with BTP-PEG10000 allowed simultaneous imaging of the tumor microvasculature and quantification of oxygen partial pressures. From lifetime images using the red-emitting intracellular oxygen probe BTPDM1 and the green-emitting intravascular fluorescent probe FITC-dextran, we demonstrated hypoxic heterogeneity in the TME with a sparse vascular network and showed that the oxygen levels of tumor cells gradually decreased with vascular distance.


Asunto(s)
Microscopía Confocal , Oxígeno , Animales , Oxígeno/metabolismo , Ratones , Humanos , Microscopía Confocal/métodos , Línea Celular Tumoral , Iridio/química , Microambiente Tumoral , Polietilenglicoles/química , Ratones Desnudos , Colorantes Fluorescentes/química , Neoplasias/diagnóstico por imagen , Neoplasias/patología
19.
Sci Data ; 11(1): 870, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-39127782

RESUMEN

Iridium(III) complexes nowadays became rising stars in various health-related applications. Thus, there is a necessity to assess cytotoxicity of the synthesized molecules against cancer/normal cell lines. In this report, we present a dataset of 2694 experimental cytotoxicity values of 803 iridium complexes against 127 different cell lines. We specify the experimental conditions and provide representation of the complexes molecules in machine-readable format. The dataset provides a starting point for exploration of new iridium-based cellular probes and opens new possibilities for predictions of toxicities and data-driven generation of new organometallic anticancer agents.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Iridio , Iridio/química , Humanos , Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Línea Celular , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales
20.
Talanta ; 280: 126776, 2024 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-39216420

RESUMEN

Cortisol is a well-known stress biomarker; this study focuses on using electrochemical immuno-sensing to measure the concentration of cortisol selectively and sensitively in artificial samples. Anti-cortisol antibodies have been immobilised on polycrystalline Au electrodes via strong covalent thiol bonds, fabricating an electrochemical bio-immunosensor for cortisol detection. IrOx was then anodically electrodeposited as a reference electrode on a commercial screen-printed electrode and electrochemical impedance spectrometry (EIS) studies were used to correlate the electrochemical response to cortisol concentration and the induced changes in charge transfer resistance (Rct). A linear relationship between the Rct and the logarithm of cortisol concentration was found in concentrations ranging from 1 ng/mL to 1 mg/mL with limit of detection at 11.85 pg/mL (32.69 pM). The modification of the reference electrode with iridium oxide has greatly improved the reproducibility of the screen-printed electrode. The sensing system can provide a reliable and sensitive detection approach for cortisol measurements.


Asunto(s)
Técnicas Electroquímicas , Electrodos , Hidrocortisona , Iridio , Hidrocortisona/análisis , Iridio/química , Técnicas Electroquímicas/instrumentación , Técnicas Electroquímicas/métodos , Sistemas de Atención de Punto , Humanos , Límite de Detección , Oro/química , Técnicas Biosensibles/métodos
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