RESUMEN
Graphite carbon nitride (g-C3N4) is a two-dimensional nano-sheet with electronic properties, which shows unique characteristics with high chemical and thermal stability in its structure. The functionalization of these compounds through covalent bonding is an important step towards significantly improving their properties and capabilities. To achieve this goal, a novel strategy for the covalent functionalization of Fe3O4@g-C3N4 with thiamine hydrochloride (vitamin B1) via cyanuric chloride (TCT), which is a divalent covalent linker, was presented. The efficiency of Fe3O4@gC3N4@Thiamine as a heterogeneous organic catalyst in the synthesis of spirooxindole-pyran derivatives and 2-amino-4H-pyran under solvent-free conditions was evaluated and the yields of high-purity products were presented. In addition, easy recycling and reuse for seven consecutive cycles without significant reduction in catalytic activity are other features of this catalyst. Moreover, the performance of the prepared sorbent in the microextraction technique (herein, magnetic solid phase extraction) was studied. The tebuconazole was selected as the target analyte. The target analyte was extracted and determined by HPLC-UV. Under the optimum condition, the linear range of the method (LDR) was estimated in the range of 0.2-100 µg L-1 (the coefficient of determination of 0.9962 for tebuconazole). The detection limit (LOD) of the method for tebuconazole was calculated to be 0.05 µg L-1. The limit of quantification (LOQ) of the method was also estimated to be 0.16 µg L-1. In order to check the precision of the proposed method, the intra-day and inter-day relative standard deviations (RSD%) were calculated, which were in the range of 1.5- 2.8%. The method was used for the successful extraction and determination of tebuconazole in tomato, cucumber, and carrot samples.
Asunto(s)
Grafito , Tiamina , Triazoles , Catálisis , Triazoles/química , Triazoles/análisis , Grafito/química , Tiamina/química , Tiamina/análisis , Contaminación de Alimentos/análisis , Análisis de los Alimentos/métodos , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Compuestos de Nitrógeno/química , Microextracción en Fase Sólida/métodos , Compuestos Inorgánicos de Carbono/químicaRESUMEN
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 & inhibidoresRESUMEN
Cyclic organic compounds containing sulfur atoms constitute a large group, and they play an important role in the chemistry of heterocyclic compounds. They are valuable intermediates for the synthesis of other compounds or biologically active compounds themselves. The synthesis of heterocyclic compounds poses a major challenge for organic chemists, especially in the context of applying the principles of "green chemistry". This work is a review of the methods of synthesis of various S-heterocyclic compounds using green solvents such as water, ionic liquids, deep eutectic solvents, glycerol, ethylene glycol, polyethylene glycol, and sabinene. The syntheses of five-, six-, and seven-membered heterocyclic compounds containing a sulfur atom or atoms, as well as those with other heteroatoms and fused-ring systems, are described. It is shown that using green solvents determines the attractiveness of conditions for many reactions; for others, such use constitutes a real compromise between efficiency and mild reaction conditions.
Asunto(s)
Tecnología Química Verde , Compuestos Heterocíclicos , Solventes , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Solventes/química , Tecnología Química Verde/métodos , Líquidos Iónicos/química , Técnicas de Química SintéticaRESUMEN
Multidrug-resistant (MDR) bacterial infections are becoming a life-threatening issue in public health; therefore, it is urgent to develop novel antibacterial agents for treating infections caused by MDR bacteria. The 20(S)-protopanaxadiol (PPD) derivative 9 was identified as a novel antibacterial hit compound in screening of our small synthetic natural product-like (NPL) library. A series of novel PPD derivatives with heterocyclic rings fused at the C-2 and C-3 positions of the A-ring were synthesized and their antibacterial activities against Staphylococcus aureus (S. aureus) Newman strain and MDR S. aureus strains (USA300, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, XJ017, and XJ036) were evaluated. Among these compounds, quinoxaline derivative 56 (SH617) exhibited the highest activity with MICs of 0.5-4 µg/mL against the S. aureus Newman strain and the eight MDR S. aureus strains. Its antibacterial activity was comparable to that of the positive control, vancomycin. In the zebrafish, 56 revealed no obvious toxicity even at a high administered dose. In vivo, following a lethal infection induced by USA300 strains in zebrafish, 56 exhibited significantly increased survival rates in a dose-dependent manner.
Asunto(s)
Antibacterianos , Pruebas de Sensibilidad Microbiana , Sapogeninas , Staphylococcus aureus , Pez Cebra , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Sapogeninas/farmacología , Sapogeninas/química , Sapogeninas/síntesis química , Staphylococcus aureus/efectos de los fármacos , Animales , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis químicaRESUMEN
The history of effective anti-cancer medications begins with the discovery of cisplatin's anti-cancer properties. Second-generation analogue, carboplatin, with a similar range of effectiveness, made progress in improving these drugs with fewer side effects and better solubility. Renewed interest in platinum-based drugs has been increasing in the past several years. These developments highlight a revitalized enthusiasm and ongoing exploration in platinum chemotherapy based on the series of dinuclear platinum(II) complexes, [{Pt(L)Cl}2(µ-bridging ligand)]2+, which have been synthesized and evaluated for their biological activities. These complexes are designed to target various cancerous conditions, exhibiting promising antitumor, antiproliferative, and apoptosis-inducing activities. The current work aims to shed light on the potential of these complexes as next-generation platinum-based therapies, highlighting their enhanced efficacy and reduced side effects, which could revolutionize the approach to chemotherapy.
Asunto(s)
Antineoplásicos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Ligandos , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/síntesis química , Apoptosis/efectos de los fármacos , Platino (Metal)/química , Platino (Metal)/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patologíaRESUMEN
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 fármacosRESUMEN
Metal complexes showing dual activity against cancer and bacterial infections are currently the focus of significant interest for their potential in treating life-threatening diseases. Aiming to investigate the impact of ligand substituents on these bioactivity properties of Group 11 d10 metal complexes, we herein present a series of mononuclear Cu(I) and Ag(I) complexes featuring the bis-NH2-substituted heterocyclic thioamide dap2SH (=4,6-diaminopyrimidine-2-thione), namely [AgCl(dap2SH)(PPh3)2] (1), [CuBr(dap2SH)(PPh3)2] (2), [CuBr(dap2SH)(xantphos)] (3), [Ag(dap2S)(xantphos)] (4), and [Cu(dap2S)(xantphos)] (5) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). Complexes were characterized by means of different physicochemical methods (i.e., single crystal X-ray diffraction as well as FTIR, NMR, UV-Vis and fluorescence spectroscopy), and studied in-vitro for their antibacterial and anticancer activity against a variety of bacterial strains and cancer cell lines. Complexes 1-3 effectively inhibited both Gram (+) and Gram (-) bacterial growth, while cellular uptake studies for the most potent complex 1 against E. coli bacteria revealed the accumulation of Ag(I) ions in the periplasm of the bacteria. A high anti-proliferative effect was observed for 1 and 5 against A549, MCF7 and PC3 cancer cell lines, with 1 being capable of inducing apoptosis in A549 cells, as suggested by flow cytometry analysis. DNA interaction studies revealed the capacity of 1 to intercalate between base-pairs of CT DNA. All complexes had a moderate-to-high capacity to scavenge free radicals preventing oxidative stress. Molecular docking calculations, in combination with the experimentally obtained data, provided insights for potential mechanisms of the bioactivity of the complexes.
Asunto(s)
Antibacterianos , Antineoplásicos , Complejos de Coordinación , Cobre , Ensayos de Selección de Medicamentos Antitumorales , Escherichia coli , Pruebas de Sensibilidad Microbiana , Plata , Tioamidas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Escherichia coli/efectos de los fármacos , Humanos , Cobre/química , Cobre/farmacología , Tioamidas/química , Tioamidas/farmacología , Tioamidas/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Plata/química , Plata/farmacología , Estructura Molecular , Relación Estructura-Actividad , Aminas/química , Aminas/farmacología , Aminas/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis químicaRESUMEN
The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors. These factors tremendously influenced understanding human health and illness, specifically cancer. Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer. Many JAK inhibitors are now being studied due to their efficacy in various cancer treatments. Further, the Nitrogen-heterocyclic (N-heterocyclic) scaffold has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics. The review focuses on several FDA-approved JAK inhibitors and their systematic categorization. The medicinal chemistry perspective is highlighted and classified review on the basis of N-heterocyclic molecules. Several examples of designing strategies of N-heterocyclic rings including pyrrolo-azepine, purine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrazole, thieno[3,2-d] pyrimidine, and, pyrimidine-based derivatives and their structure-activity relationships (SAR) are discussed. Among the various N-heterocyclic-based JAK inhibitors pyrimidine-containing compound 1 exhibited excellent inhibition activity against JAK2WT and mutated-JAK2V617F with IC50 of 2.01 and 18.84 nM respectively. Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.
Asunto(s)
Antineoplásicos , Compuestos Heterocíclicos , Inhibidores de las Cinasas Janus , Animales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/química , Inhibidores de las Cinasas Janus/síntesis química , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Estructura Molecular , Neoplasias/tratamiento farmacológico , Nitrógeno/química , Relación Estructura-Actividad , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacologíaRESUMEN
A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.
Asunto(s)
Antineoplásicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB , Inhibidores de Proteínas Quinasas , Quinazolinas , Receptor ErbB-2 , Humanos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Quinazolinas/farmacología , Quinazolinas/química , Quinazolinas/síntesis química , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Animales , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Ratones , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Apoptosis/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , FemeninoRESUMEN
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 químicaRESUMEN
Since the largest and most fatal Ebola virus epidemic during 2014-2016, there have been several consecutive filoviral outbreaks in recent years, including those in 2021, 2022, and 2023. Ongoing outbreak prevalence and limited FDA-approved filoviral therapeutics emphasize the need for novel small molecule treatments. Here, we showcase the structure-activity relationship development of N-substituted pyrrole-based heterocycles and their potent, submicromolar entry inhibition against diverse filoviruses in a target-based pseudovirus assay. Inhibitor antiviral activity was validated using replication-competent Ebola, Sudan, and Marburg viruses. Mutational analysis was used to map the targeted region within the Ebola virus glycoprotein. Antiviral counter-screen and phospholipidosis assays were performed to demonstrate the reduced off-target activity of these filoviral entry inhibitors. Favorable antiviral potency, selectivity, and drug-like properties of the N-substituted pyrrole-based heterocycles support their potential as broad-spectrum antifiloviral treatments.
Asunto(s)
Antivirales , Ebolavirus , Pirroles , Internalización del Virus , Pirroles/farmacología , Pirroles/química , Pirroles/síntesis química , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Humanos , Relación Estructura-Actividad , Ebolavirus/efectos de los fármacos , Internalización del Virus/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Filoviridae/efectos de los fármacos , Marburgvirus/efectos de los fármacosRESUMEN
This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a-5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a "click chemistry" approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of -9.9 and -9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski's criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development.
Asunto(s)
Benzoxazinas , Inhibidores de Glicósido Hidrolasas , Simulación del Acoplamiento Molecular , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/síntesis química , Benzoxazinas/química , Benzoxazinas/farmacología , Benzoxazinas/síntesis química , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , alfa-Amilasas Pancreáticas/antagonistas & inhibidores , alfa-Amilasas Pancreáticas/metabolismo , Reacción de Cicloadición , Estructura Molecular , Simulación por Computador , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Humanos , Relación Estructura-Actividad , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo , alfa-Amilasas/química , Intestinos/enzimologíaRESUMEN
Antagonism of the human adenosine A3 receptor (hA3R) has potential therapeutic application. Alchemical relative binding free energy calculations of K18 and K32 suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hA3R affinity. Of the 25 new analogues synthesized, 37 and 74 showed improved hA3R affinity compared to K18 (and K32). This was further improved through the addition of a bromine group to the 2-pyridinyl at the 5-position, generating compound 39. Alchemical relative binding free energy calculations, mutagenesis studies and MD simulations supported the compounds' binding pattern while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, so highlighting the importance of rigidification of the carbonyloxycarboximidamide moiety. MD simulations highlighted the importance of rigidification of the carbonyloxycarboximidamide, while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, which was supported through mutagenesis studies 39 also selectively antagonized endogenously expressed hA3R in nonsmall cell lung carcinoma cells, while pharmacokinetic studies indicated low toxicity enabling in vivo evaluation. We therefore suggest that 39 has potential for further development as a high-affinity hA3R antagonist.
Asunto(s)
Antagonistas del Receptor de Adenosina A3 , Receptor de Adenosina A3 , Humanos , Receptor de Adenosina A3/metabolismo , Receptor de Adenosina A3/química , Relación Estructura-Actividad , Animales , Antagonistas del Receptor de Adenosina A3/farmacología , Antagonistas del Receptor de Adenosina A3/química , Antagonistas del Receptor de Adenosina A3/síntesis química , Simulación de Dinámica Molecular , Ratas , Células CHO , Línea Celular Tumoral , Cricetulus , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis químicaRESUMEN
Guided by the X-ray cocrystal structure of the lead compound 4a, we developed a series of thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines demonstrating potent antiproliferative activity against four tumor cell lines. Two analogs, 13 and 25d, exhibited IC50 values around 1 nM and overcame P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). At low concentrations, 13 and 25d inhibited both the colony formation of SKOV3 cells in vitro and tubulin polymerization. Furthermore, mechanistic studies showed that 13 and 25d induced G2/M phase arrest and apoptosis in SKOV3 cells, as well as dose-dependent inhibition of tumor cell migration and invasion at low concentrations. Most notably, the X-ray cocrystal structures of compounds 4a, 25a, and the optimal molecule 13 in complex with tubulin were elucidated. This study identifies thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines as representatives of colchicine-binding site inhibitors (CBSIs) with potent antiproliferative activity.
Asunto(s)
Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Pirimidinas , Moduladores de Tubulina , Tubulina (Proteína) , Humanos , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Relación Estructura-Actividad , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/síntesis química , Estructura Molecular , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Descubrimiento de Drogas , Modelos MolecularesRESUMEN
Nitrogen-containing steroids are known as prostate cancer therapeutics. In this work, a series of pregnane derivatives bearing an imidazolium moiety were synthesized using Δ16-20-ketones as starting material. An improved approach for the construction of the 20-keto-21-heterocycle-substituted fragment involved the rearrangement of 16,17-epoxides with HCl, followed by reaction of the formed α-chloroketone with 1-substituted imidazoles. Binding affinity analysis of the imidazolium steroids and their synthetic intermediates to human CYP17A1 showed only type I (substrate-like) interactions. The strongest affinity was observed for 16α,17α-epoxy-5α-pregnan-20-on-3ß-ol (Kd = 0.66 ± 0.05 µM). The steroid derivatives have been evaluated for antitumor activity against a range of prostate cancer cells as well as against various other solid tumor and hematologic cancer cell lines. All 21-imidazolium salts were active against the hormone-dependent prostate cancer line LNCaP. The most pronounced cytotoxicity in solid tumor and hematologic cancer cell lines was observed for intermediate product, 21-chloro-5α-pregn-16-en-20-on-3ß-ol. Among the imidazolium salts, the derivatives with a single bond were more cytotoxic than their unsaturated congeners.
Asunto(s)
Antineoplásicos , Imidazoles , Humanos , Masculino , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Imidazoles/química , Imidazoles/farmacología , Imidazoles/síntesis química , Sales (Química)/química , Sales (Química)/farmacología , Sales (Química)/síntesis química , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Esteroide 17-alfa-Hidroxilasa/metabolismo , Esteroides/química , Esteroides/farmacología , Esteroides/síntesis química , Relación Estructura-Actividad , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacologíaRESUMEN
A series of novel five-membered sulfur-containing heterocyclic nucleoside derivatives were designed, synthesized, and evaluated for their anticancer activities in vitro and in vivo. The structure-activity relationship studies revealed that some of them showed obvious antitumor activities in several cancer cell lines. Among them, compound 22o exhibited remarkable antiproliferative activity against HeLa cells and was more potent than cisplatin (IC50 = 2.80 vs 7.99 µM). Furthermore, mechanism studies indicated that 22o inhibited cell metastasis, induced cell apoptosis, decreased mitochondrial membrane potential, and activated autophagy through the PI3K-Akt-mTOR signaling pathway. Moreover, drug affinity responsive target stability and the cellular thermal shift assay revealed that 22o targeted RPS6 and inhibited its phosphorylation. Importantly, 22o inhibited the growth of the HeLa xenograft mouse model with a low systemic toxicity. These results indicated that 22o may serve as potent anticancer agents that merit further attention in future anticancer drug discovery.
Asunto(s)
Antineoplásicos , Proliferación Celular , Nucleósidos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Animales , Relación Estructura-Actividad , Nucleósidos/síntesis química , Nucleósidos/farmacología , Nucleósidos/química , Ratones , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Línea Celular Tumoral , Ratones Desnudos , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Azufre/química , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.
Asunto(s)
Antineoplásicos , Etilenos , Compuestos Heterocíclicos , Cetonas , Humanos , Línea Celular Tumoral , Etilenos/química , Etilenos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Relación Estructura-Actividad , Histona Desacetilasas/metabolismo , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Acetales/química , Acetales/farmacología , Acetales/síntesis química , Proteínas RepresorasRESUMEN
The versatile reactivity of isothiocyanate intermediates enabled the diversity-oriented synthesis (DOS) of N-heterocycles in a DNA-compatible manner. We first reported a mild in situ conversion of DNA-conjugated amines to isothiocyanates. Subsequently, a set of diverse transformations was successfully developed to construct 2-thioxo-quinazolinones, 1,2,4-thiadiazoles, and 2-imino thiazolines. Finally, the feasibility of these approaches in constructing DELs was further demonstrated through enzymatic ligation and mock pool preparation. This study demonstrated the advantages of combining in situ conversion strategies with DOS, which effectively broadened the chemical and structural diversity of DELs.
Asunto(s)
ADN , Compuestos Heterocíclicos , Isotiocianatos , Isotiocianatos/química , ADN/química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Estructura Molecular , Aminas/química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/síntesis químicaRESUMEN
The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles.
Asunto(s)
Antineoplásicos , Azoles , Compuestos Ferrosos , Compuestos Heterocíclicos , Metalocenos , Azoles/química , Azoles/farmacología , Azoles/síntesis química , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Compuestos Ferrosos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Humanos , Metalocenos/química , Metalocenos/farmacología , Metalocenos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis químicaRESUMEN
Cumulative escalation in antibiotic-resistant pathogens necessitates the quest for novel antimicrobial agents, as current options continue to diminish bacterial resistance. Herein, we report the synthesis of di-heterocyclic benzazole structures (12-19) and their in vitro evaluation for some biological activities. Compounds 16 and 17 demonstrated potent antibacterial activity (MIC = 7.81 µg/mL) against Staphylococcus aureus, along with significant anti-biofilm activity. Noteworthy is the capability of Compound 17 to inhibit biofilm formation by at least 50% at sub-MIC (3.90 µg/mL) concentration. Furthermore, both compounds exhibited the potential to inhibit preformed biofilm by at least 50% at the MIC concentration (7.81 µg/mL). Additionally, Compounds 16 and 17 were examined for cytotoxic effects in HFF-1 cells, using the MTT method, and screened for binding interactions within the active site of S. aureus DNA gyrase using in silico molecular docking technique, employing AutoDock 4.2.6 and Schrödinger Glidse programs. Overall, our findings highlight Compounds 16 and 17 as promising scaffolds warranting further optimization for the development of effective antibacterial and anti-biofilm agents.