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1.
Org Lett ; 26(41): 8872-8877, 2024 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-39387534

RESUMEN

Organoborons have recently received much attention, while a biocatalytic platform for the synthesis of chiral organoborons is limited only to Rma cytochrome c. In this study, we exploited the other heme protein, neuroglobin (Ngb), and engineered a quadruple mutant, A15C/H64G/V68F/F28M Ngb, by redesigning the heme active site using the structural information on A15C Ngb and molecular docking studies. The enzyme was shown to be efficient in catalyzing carbene transfer B-H insertion reactions between pyridine/quinoline boranes and benzyl 2-diazopropanoates and their derivatives (29 examples). The designed cavity in the heme distal site favors the binding of large volume substrates such as those containing a quinoline, naphthyl, or biphenyl group. As further determined by the X-ray crystallography of 6c, the chiral products are in the R-configuration, with up to 98:2 e.r. Furthermore, both the whole cell and cell lysate containing the enzyme are reactive toward the B-H insertion reactions. This study presents a convenient biocatalytic platform that may be generally applicable for the synthesis of functional chiral organoborons.


Asunto(s)
Metano , Neuroglobina , Neuroglobina/metabolismo , Neuroglobina/química , Metano/análogos & derivados , Metano/química , Estructura Molecular , Cristalografía por Rayos X , Estereoisomerismo , Simulación del Acoplamiento Molecular , Compuestos de Boro/química , Compuestos de Boro/síntesis química , Quinolinas/química , Quinolinas/síntesis química , Quinolinas/metabolismo , Ingeniería de Proteínas , Dominio Catalítico
2.
Int J Mol Sci ; 25(17)2024 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-39273150

RESUMEN

A new eco-friendly method for the synthesis of mono- and multifunctional organosulfur compounds, based on the process between ynals and thiols, catalyzed by bulky N-heterocyclic carbene (NHC), was designed and optimized. The proposed organocatalytic approach allows the straightforward formation of a broad range of thioesters and sulfenyl-substituted aldehydes in yields above 86%, in mild and metal-free conditions. In this study, thirty-six sulfur-based derivatives were obtained and characterized by spectroscopic methods.


Asunto(s)
Aldehídos , Compuestos de Sulfhidrilo , Compuestos de Sulfhidrilo/química , Aldehídos/química , Catálisis , Metano/química , Metano/análogos & derivados , Tecnología Química Verde/métodos
3.
Medicina (Kaunas) ; 60(9)2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39336420

RESUMEN

Background and Objectives: Colorectal cancer (CRC) remains a major global health issue. Although chemotherapy is the first-line treatment, its effectiveness is limited due to drug resistance developed in CRC. To overcome resistance and improve the prognosis of CRC patients, investigating new therapeutic approaches is necessary. Materials and Methods: Using human colorectal adenocarcinoma (HT29) and metastatic CRC (SW620) cell lines, the potential anticancer properties of a newly synthesized compound 1-(Isobutyl)-3-(4-methylbenzyl) benzimidazolium chloride (IMBZC) were evaluated by performing MTT cytotoxicity, cell migration, and colony formation assays, as well as by monitoring apoptosis-related protein and gene expression using Western blot and reverse transcription-quantitative polymerase chain reaction technologies. Results: Tested at various concentrations, the half-maximal inhibitory concentrations (IC50) of IMBZC on HT29 and SW620 cell growth were determined to be 22.13 µM (6.97 µg/mL) and 15.53 µM (4.89 µg/mL), respectively. IMBZC did not alter the cell growth of normal HEK293 cell lines. In addition, IMBZC inhibited cell migration and significantly decreased colony formation, suggesting its promising role in suppressing cancer metastasis. Mechanistic analyses revealed that IMBZC treatment increased the expression of pro-apoptotic proteins p53 and Bax, while decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, thus indicating the induction of apoptosis in IMBZC-treated CRC cells, compared to untreated cells. Additionally, the addition of IMBZC to conventional chemotherapeutic drugs (i.e., 5-fluorouracil, irinotecan, and oxaliplatin) resulted in an increase in the cytotoxic potential of the drugs. Conclusions: This study suggests that IMBZC has substantial anticancer effects against CRC cells through its ability to induce apoptosis, inhibit cancer cell migration and colony formation, and enhance the cytotoxic effects of conventional chemotherapeutic drugs. These findings indicate that IMBZC could be a promising chemotherapeutic drug for the treatment of CRC. Further research should be conducted using in vivo models to confirm the anti-CRC activities of IMBZC.


Asunto(s)
Antineoplásicos , Apoptosis , Bencimidazoles , Proliferación Celular , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Metano/farmacología , Metano/análogos & derivados , Metano/uso terapéutico
4.
Inorg Chem ; 63(37): 16949-16963, 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39226133

RESUMEN

A series of new gold(I) and silver(I) N-heterocyclic carbenes bearing a 1-thio-ß-d-glucose tetraacetate moiety was synthesized and chemically characterized. The compounds' stability and solubility in physiological conditions were investigated employing a multitechnique approach. Interaction studies with biologically relevant proteins, such as superoxide dismutase (SOD) and human serum albumin (HSA), were conducted via UV-vis absorption spectroscopy and high-resolution ESI mass spectrometry. The biological activity of the compounds was evaluated in the A2780 and A2780R (cisplatin-resistant) ovarian cancer cell lines and the HSkMC (human skeletal muscle) healthy cell line. Inhibition studies of the selenoenzyme thioredoxin reductase (TrxR) were also carried out. The results highlighted that the gold complexes are more stable in aqueous environment and capable of interaction with SOD and HSA. Moreover, these carbenes strongly inhibited the TrxR activity. In contrast, the silver ones underwent structural alterations in the aqueous medium and showed greater antiproliferative activity.


Asunto(s)
Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Oro , Compuestos Heterocíclicos , Metano , Plata , Reductasa de Tiorredoxina-Disulfuro , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Plata/química , Plata/farmacología , Oro/química , Oro/farmacología , Metano/análogos & derivados , Metano/química , Metano/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Proliferación Celular/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Estructura Molecular , Relación Estructura-Actividad , Línea Celular Tumoral , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/antagonistas & inhibidores
5.
Int J Biol Macromol ; 279(Pt 4): 135386, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39245122

RESUMEN

Because of eco-friendliness, biodegradability and ease of modification, cellulose is deemed as alternative to unrenewable petroleum resources. Nonetheless, it is more indispensable to exploit corn cob cellulose produced from agricultural waste residue as supportive materials in green catalysis. In this study, a new magnetically benzimidazole functionalized cellulose/Fe3O4 derived from corn cob cellulose as a stabilizer agent (Fe3O4@CL-NHC) was prepared, and palladium was immobilized on this stabilizer (Fe3O4@CL-NHC-Pd). The catalyst was fully characterized by different techniques including TEM, SEM, and XPS analyses, etc. The abundant hydroxyl groups of cellulose provided uniform dispersion and high stability of palladium, while Fe3O4 as a support offered simple magnetic separation. High efficiency (up to 99 %) was demonstrated by this biocatalyst under green conditions in relatively short reaction times towards Suzuki reactions. Due to collaborative interactions of N-heterocyclic carbene and hydroxyl groups with palladium, the synthesized complex prevented metal leaching effectively (<1 %). Moreover, the magnetic property of this catalyst (43.0 emu g-1) provides facile recovery of this composite from the reaction mixture with great ease for several times, which overcomes issues of complicated work-up separation. This work offers a promising avenue to enriching the application of biopolymer from agricultural residue in the potential organic transformations.


Asunto(s)
Celulosa , Metano , Paladio , Zea mays , Paladio/química , Catálisis , Zea mays/química , Celulosa/química , Metano/química , Metano/análogos & derivados , Agricultura , Compuestos Heterocíclicos/química , Fenómenos Magnéticos
6.
Molecules ; 29(17)2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39275023

RESUMEN

The reaction between glycine-type aminonaphthol derivatives substituted with 2- or 1-naphthol and indole or 7-azaindole has been tested. Starting from 2-naphthol as a precursor, the reaction led to the formation of ring-closed products, while in the case of a 1-naphthol-type precursor, the desired biaryl ester was isolated. The synthesis of a bifunctional precursor starting from 5-chloro-8-hydroxyquinoline, morpholine, and ethyl glyoxylate via modified Mannich reaction is reported. The formed Mannich base 10 was subjected to give bioconjugates with indole and 7-azaindole. The effect of the aldehyde component and the amine part of the Mannich base on the synthetic pathway was also investigated. In favor of having a preliminary overview of the structure-activity relationships, the derivatives have been tested on cancer and normal cell lines. In the case of bioconjugate 16, as the most powerful scaffold in the series bearing indole and a 5-chloro-8-hydroxyquinoline skeleton, a potent toxic activity against the resistant Colo320 colon adenocarcinoma cell line was observed. Furthermore, this derivative was selective towards cancer cell lines showing no toxicity on non-tumor fibroblast cells.


Asunto(s)
Antineoplásicos , Indoles , Humanos , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Relación Estructura-Actividad , Oxiquinolina/química , Oxiquinolina/farmacología , Metano/química , Metano/análogos & derivados , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales
7.
Eur J Med Chem ; 277: 116757, 2024 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-39142149

RESUMEN

N-heterocyclic carbenes (NHCs) represent suitable ligands for rapid and efficient drug design, because they offer the advantage of being easily chemically modified and can bind several substituents, including transition metals as, for instance, gold derivatives. Gold-NHC complexes possess various biological activities and were demonstrated good candidates as anticancer drugs. Besides, carbazole derivatives are characterized by various pharmacological properties, such as anticancer, antibacterial, anti-inflammatory, and anti-psychotropic. Amongst the latter, N-thioalkyl carbazoles were proved to inhibit cancer cells damaging the nuclear DNA, through the inhibition of human topoisomerases. Herein, we report the design, synthesis and biological evaluation of nine new hybrid molecules in which NHC-Au(I) complexes and N-alkylthiolated carbazoles are linked together, in order to obtain novel biological multitarget agents. We demonstrated that the lead hybrid complexes possess anticancer, anti-inflammatory and antioxidant properties, with a high potential as useful tools for treating distinct aspects of several diseases, amongst them cancer.


Asunto(s)
Antineoplásicos , Carbazoles , Diseño de Fármacos , Compuestos Heterocíclicos , Metano , Carbazoles/química , Carbazoles/farmacología , Carbazoles/síntesis química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Relación Estructura-Actividad , Metano/análogos & derivados , Metano/química , Metano/farmacología , Estructura Molecular , Oro/química , Oro/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Animales , Relación Dosis-Respuesta a Droga , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química
8.
Int J Biol Macromol ; 278(Pt 2): 134756, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39147340

RESUMEN

An attractive strategy for efficiently forming CS bonds is through the use of diazo compounds SH insertion. However, achieving good enantioselective control in this reaction within a biocatalytic system has proven to be challenging. This study aimed to enhance the activity and enantioselectivity of to enable asymmetric SH insertion. The researchers conducted site-saturation mutagenesis (SSM) on 5 amino acid residues located around the iron carbenoid intermediate within a distance of 5 Å, followed by iterative saturation mutagenesis (ISM) of beneficial mutants. Through this process, the beneficial variant VHbSH(P54R/V98W) was identified through screening with 4-(methylmercapto) phenol as the substrate. This variant exhibited up to 4-fold higher catalytic efficiency and 6-fold higher enantioselectivity compared to the wild-type VHb. Computational studies were also conducted to elucidate the detailed mechanism of this asymmetric SH insertion, explaining how active-site residues accelerate this transformation and provide stereocontrol.


Asunto(s)
Proteínas Bacterianas , Ingeniería de Proteínas , Hemoglobinas Truncadas , Hemoglobinas Truncadas/genética , Hemoglobinas Truncadas/química , Hemoglobinas Truncadas/metabolismo , Ingeniería de Proteínas/métodos , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Estereoisomerismo , Especificidad por Sustrato , Metano/química , Metano/análogos & derivados , Metano/metabolismo , Mutagénesis Sitio-Dirigida , Modelos Moleculares , Dominio Catalítico , Biocatálisis
9.
J Inorg Biochem ; 260: 112688, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39111220

RESUMEN

New-to-Nature biocatalysis has emerged as a promising tool in organic synthesis thanks to progress in protein engineering. Notably, hemeproteins have been evolved into robust catalysts for carbene and nitrene transfers and related sigmatropic rearrangements. In this work, we report the first example of a [2,3]-sigmatropic Sommelet-Hauser rearrangement initiated by a carbene transfer of the sperm whale myoglobin mutant L29S,H64V,V68F that was previously reported to catalyze the mechanistically similar [2,3]-sigmatropic Doyle-Kirmse rearrangement. This repurposed heme enzyme catalyzes the Sommelet-Hauser rearrangement between ethyl diazoacetate and benzyl thioethers bearing strong electron-withdrawing substituents with good yields and enantiomeric excess. Optimized catalytic conditions in the absence of any reductant led to an increased asymmetric induction with up to 59% enantiomeric excess. This myoglobin mutant is therefore one of the few catalysts for the asymmetric Sommelet-Hauser rearrangement. This work broadens the scope of abiological reactions catalyzed by iron-carbene transferases with a new example of asymmetric sigmatropic rearrangement.


Asunto(s)
Mioglobina , Mioglobina/química , Mioglobina/genética , Mioglobina/metabolismo , Metano/análogos & derivados , Metano/química , Metano/metabolismo , Biocatálisis , Transferasas/metabolismo , Transferasas/genética , Transferasas/química , Animales , Cachalote , Ingeniería de Proteínas/métodos
10.
J Chem Phys ; 161(5)2024 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-39087548

RESUMEN

In this study, peptides designed using fragments of an antifreeze protein (AFP) from the freeze-tolerant insect Tenebrio molitor, TmAFP, were evaluated as inhibitors of clathrate hydrate formation. It was found that these peptides exhibit inhibitory effects by both direct and indirect mechanisms. The direct mechanism involves the displacement of methane molecules by hydrophobic methyl groups from threonine residues, preventing their diffusion to the hydrate surface. The indirect mechanism is characterized by the formation of cylindrical gas bubbles, the morphology of which reduces the pressure difference at the bubble interface, thereby slowing methane transport. The transfer of methane to the hydrate interface is primarily dominated by gas bubbles in the presence of antifreeze peptides. Spherical bubbles facilitate methane migration and potentially accelerate hydrate formation; conversely, the promotion of a cylindrical bubble morphology by two of the designed systems was found to mitigate this effect, leading to slower methane transport and reduced hydrate growth. These findings provide valuable guidance for the design of effective peptide-based inhibitors of natural-gas hydrate formation with potential applications in the energy and environmental sectors.


Asunto(s)
Proteínas Anticongelantes , Metano , Tenebrio , Agua , Proteínas Anticongelantes/química , Cinética , Metano/química , Metano/análogos & derivados , Agua/química , Tenebrio/química , Animales , Gases/química , Péptidos/química , Péptidos/farmacología
11.
J Med Chem ; 67(16): 14414-14431, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39119630

RESUMEN

In this study, we synthesized novel Pd(II)-indenyl complexes using various N-heterocyclic carbene (NHC) ligands, including chelating NHC-picolyl, NHC-thioether, and diNHC ligands, and two monodentate NHCs. Transmetalation reactions between a Pd(II)-indenyl precursor and silver-NHC complexes were generally employed, except for chelating diNHC derivatives, which required direct reaction with bisimidazolium salts and potassium carbonate. Characterization included NMR, HRMS analysis, and single-crystal X-ray diffraction. In vitro on five ovarian cancer cell lines showed notable cytotoxicity, with IC50 values in the micro- and submicromolar range. Some compounds exhibited intriguing selectivity for cancer cells due to higher tumor cell uptake. Mechanistic studies revealed that monodentate NHCs induced mitochondrial damage while chelating ligands caused DNA damage. One chelating NHC-picolyl ligand showed promising cytotoxicity and selectivity in high-grade serous ovarian cancer models, supporting its consideration for preclinical study.


Asunto(s)
Antineoplásicos , Compuestos Heterocíclicos , Metano , Neoplasias Ováricas , Paladio , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Paladio/química , Metano/análogos & derivados , Metano/química , Metano/farmacología , Ligandos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Indenos/química , Indenos/farmacología , Indenos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad
12.
J Med Chem ; 67(17): 15494-15508, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39196554

RESUMEN

From previous studies, it is evident that metal-organic gold(I) complexes have antiproliferative activities. The aim of this study is not only to find new anticancer agents but also to overcome existing cytostatic resistance in cancer cells. The synthesis and medicinal evaluation of two cationic 1,3-disubstituted gold(I) bis-tetrazolylidene complexes 1 and 2 are reported. To determine apoptosis-inducing properties of the complexes, DNA fragmentation was measured using propidium iodide staining followed by flow cytometry. Gold(I) complex 1 targets explicitly malignant cells, effectively inhibiting their growth and selectively inducing apoptosis without signs of necrosis. Even in cells resistant to common treatments such as doxorubicin, it overcomes multidrug resistance and sensitizes existing drug-resistant cells to common cytostatic drugs. It is assumed that gold(I) complex 1 involves the mitochondrial pathway in apoptosis and targets members of the BCL-2 family, enhancing its potential as a therapeutic agent in cancer treatment.


Asunto(s)
Antineoplásicos , Apoptosis , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Oro , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Oro/química , Oro/farmacología , Línea Celular Tumoral , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia/metabolismo , Metano/análogos & derivados , Metano/farmacología , Metano/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos
13.
Chem Rev ; 124(16): 9580-9608, 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-38953775

RESUMEN

Over 20 years ago, the pyrrolysine encoding translation system was discovered in specific archaea. Our Review provides an overview of how the once obscure pyrrolysyl-tRNA synthetase (PylRS) tRNA pair, originally responsible for accurately translating enzymes crucial in methanogenic metabolic pathways, laid the foundation for the burgeoning field of genetic code expansion. Our primary focus is the discussion of how to successfully engineer the PylRS to recognize new substrates and exhibit higher in vivo activity. We have compiled a comprehensive list of ncAAs incorporable with the PylRS system. Additionally, we also summarize recent successful applications of the PylRS system in creating innovative therapeutic solutions, such as new antibody-drug conjugates, advancements in vaccine modalities, and the potential production of new antimicrobials.


Asunto(s)
Aminoacil-ARNt Sintetasas , Código Genético , Lisina , Humanos , Aminoacil-ARNt Sintetasas/metabolismo , Aminoacil-ARNt Sintetasas/genética , Evolución Molecular , Lisina/metabolismo , Lisina/análogos & derivados , Lisina/química , Metano/análogos & derivados , Metano/metabolismo , Metano/química , Animales
14.
Nat Commun ; 15(1): 6060, 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39025860

RESUMEN

While photo-cross-linking (PXL) with alkyl diazirines can provide stringent distance restraints and offer insights into protein structures, unambiguous identification of cross-linked residues hinders data interpretation to the same level that has been achieved with chemical cross-linking (CXL). We address this challenge by developing an in-line system with systematic modulation of light intensity and irradiation time, which allows for a quantitative evaluation of diazirine photolysis and photo-reaction mechanism. Our results reveal a two-step pathway with mainly sequential generation of diazo and carbene intermediates. Diazo intermediate preferentially targets buried polar residues, many of which are inaccessible with known CXL probes for their limited reactivity. Moreover, we demonstrate that tuning light intensity and duration enhances selectivity towards polar residues by biasing diazo-mediated cross-linking reactions over carbene ones. This mechanistic dissection unlocks the full potential of PXL, paving the way for accurate distance mapping against protein structures and ultimately, unveiling protein dynamic behaviors.


Asunto(s)
Reactivos de Enlaces Cruzados , Diazometano , Diazometano/química , Reactivos de Enlaces Cruzados/química , Proteínas/química , Fotólisis , Luz , Metano/química , Metano/análogos & derivados , Conformación Proteica
15.
Dalton Trans ; 53(32): 13503-13514, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39072444

RESUMEN

Tris(pyrazolyl)methane (tpm), 2,2,2-tris(pyrazolyl)ethanol (tpmOH) and its esterification derivatives with ibuprofen and flurbiprofen (tpmIBU and tpmFLU) were used as ligands to obtain complexes of the type [Fe(tpmX)2]Cl2 (1-4). The tpmIBU and tpmFLU ligands and corresponding complexes 3 and 4 were characterized by IR and multinuclear NMR spectroscopy, and the structure of tpmIBU was elucidated by single crystal X-ray diffraction. Complexes 1-4 were also assessed for their behaviour in aqueous media (solubility in D2O, octanol/water partition coefficient, stability in physiological-like conditions). The antiproliferative activity of ligands and complexes was determined on A2780, A2780cis and A549 cancer cell lines and the non-cancerous HEK 293T and BJ cell lines. The ligands and complexes were investigated for their ability to inhibit COX-2 (cyclooxygenase) and HNE (4-hydroxynonenal) enzymes. Complexes 3 and 4 exhibited cytotoxicity that may be attributed predominantly to their bioactive fragments, while DNA binding and enhancement of ROS production do not appear to play any significant role.


Asunto(s)
Antiinflamatorios no Esteroideos , Antineoplásicos , Complejos de Coordinación , Pirazoles , Humanos , Ligandos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Metano/química , Metano/análogos & derivados , Metano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Ciclooxigenasa 2/metabolismo , Aldehídos/química , Aldehídos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estructura Molecular , Ibuprofeno/química , Ibuprofeno/farmacología , Modelos Moleculares
16.
Colloids Surf B Biointerfaces ; 242: 114097, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39067190

RESUMEN

N-Heterocyclic carbenes (NHC) are well-recognized ligands of choice for preparing robust transition metal species. However, their use for fabrication of biomedically relevant nanoparticles has been limited to the synthesis of non-targeted particles showing increased tolerance to different aqueous coagulants. In this work, the first example of carbene-coated metal nanoparticles suitable for in vivo applications is presented. Directed design of a novel biscarbene NHC ligand allowed to prepare the first magnetite/gold (Fe3O4@AuNP@NHC) nanostructures and carbene gold (AuNP@NHC) nanoparticles with significant stability in aqueous solutions and enhanced ability to form bioconjugates. Furthermore, these nanoparticles exhibit an extraordinary property for inorganic nanoparticles: they can endure several additive-free air drying/redispersion cycles without deterioration of their colloidal behavior. Bioconjugated AuNP@NHC and multimodal Fe3O4@AuNP@NHC demonstrated a successful performance in three distinct applications: lateral flow tests, specific cancer cell targeting, and bioimaging. Thus, the results show the notable advantages of the N-heterocyclic carbene coating of inorganic nanoparticles and their utility for complex biomedical applications.


Asunto(s)
Oro , Nanopartículas del Metal , Metano , Metano/química , Metano/análogos & derivados , Oro/química , Nanopartículas del Metal/química , Humanos , Tamaño de la Partícula
17.
ChemMedChem ; 19(20): e202400236, 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-38934210

RESUMEN

Intending to homogenize the biological activities of both quinoxaline and imidazole moieties, the proligand, 1-methyl-3-quinoxaline-imidazolium hexaflurophosphate (1.HPF6), and [Ag(1)2][PF6], (2); [Au(1)2][PF6], (3); and [Au(1)Cl3], (4) NHC complexes were synthesized. All the synthesized compounds were characterized by elemental analysis, NMR, and UV-Vis spectroscopy. Finally, single crystal X-ray structures revealed a linear geometry for complex 2 whereas a square planar geometry for complex 4. The formation of complex 3 was confirmed and supported by its MS spectra. The antibacterial activities of all the synthesized complexes were investigated against gram-positive bacteria and gram-negative bacteria. The Au(III)-NHC complex, 4 showed the highest antibacterial activity with extremely low MIC values against both the bacterial strains (0.24 µg mL-1). Monitoring of zeta potential supports the higher activity of complex 4 compared to 2 and 3. ROS production by complex 4 has also been measured in vitro in the CT26 cancer cell lines, which is directly responsible for targetting and killing the bacterial pathogens. Cell cytotoxicity assay using 293T cell lines has been performed to investigate the biocompatibility nature of complex 4. Also, an excellent hemocompatibility was assigned to it from its hemolytic studies, which provide valuable insights into the design of novel antibacterial agents.


Asunto(s)
Antibacterianos , Complejos de Coordinación , Diseño de Fármacos , Oro , Bacterias Gramnegativas , Bacterias Grampositivas , Metano , Pruebas de Sensibilidad Microbiana , Quinoxalinas , Plata , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Quinoxalinas/química , Quinoxalinas/farmacología , Quinoxalinas/síntesis química , Oro/química , Oro/farmacología , Humanos , Metano/análogos & derivados , Metano/química , Metano/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Plata/química , Plata/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Relación Estructura-Actividad , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Estructura Molecular , Farmacorresistencia Bacteriana/efectos de los fármacos , Relación Dosis-Respuesta a Droga
18.
Nature ; 631(8022): 789-795, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38843825

RESUMEN

The ability to tame high-energy intermediates is important for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often unknown, high-energy intermediates1,2. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the carbon-metal bond. However, these methods are usually prohibitive because of reagent safety concerns, limiting their broad implementation in synthesis3-6. Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to metal to forge the initial carbon-metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Here we realize this strategy through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N-H, S-H and P-H bonds from abundant and bench-stable carboxylic acids, amino acids and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.


Asunto(s)
Alcoholes , Aminoácidos , Ácidos Carboxílicos , Técnicas de Química Sintética , Hierro , Metano , Fotoquímica , Alcoholes/química , Aminoácidos/química , Carbono/química , Ácidos Carboxílicos/química , Catálisis , Ciclopropanos/química , Ciclopropanos/síntesis química , Hierro/química , Metano/análogos & derivados , Metano/química , Oxidación-Reducción , Fotoquímica/métodos , Técnicas de Química Sintética/métodos , Electrones
19.
Proc Natl Acad Sci U S A ; 121(25): e2316615121, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38861602

RESUMEN

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.


Asunto(s)
Antineoplásicos , Iridio , Metano , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Iridio/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metano/análogos & derivados , Metano/química , Metano/farmacología , Proteínas de Microfilamentos/metabolismo , Metástasis de la Neoplasia , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino
20.
Int J Mol Sci ; 25(12)2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38928428

RESUMEN

A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.


Asunto(s)
Antineoplásicos , Apoptosis , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Metano/análogos & derivados , Metano/química , Metano/farmacología , Proliferación Celular/efectos de los fármacos , Xantenos/farmacología , Xantenos/química
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