RESUMEN
Bovine viral diarrhea virus (BVDV) is a widespread pathogen of cattle and other mammals that causes major economic losses in the livestock industry. N4-TSC and 6NO2-TSC are two thiosemicarbazones derived from 1-indanone that exhibit anti-BVDV activity in vitro. These compounds selectively inhibit BVDV and are effective against both cytopathic and non-cytopathic BVDV-1 and BVDV-2 strains. We confirmed that N4-TSC acts at the onset of viral RNA synthesis, as previously reported for 6NO2-TSC. Moreover, resistance selection and characterization showed that N4-TSCR mutants were highly resistant to N4-TSC but remained susceptible to 6NO2-TSC. In contrast, 6NO2-TSCR mutants were resistant to both compounds. Additionally, mutations N264D and A392E were found in the viral RNA-dependent RNA polymerase (RdRp) of N4-TSCR mutants, whereas I261 M was found in 6NO2-TSCR mutants. These mutations lay in a hydrophobic pocket within the fingertips region of BVDV RdRp that has been described as a "hot spot" for BVDV non-nucleoside inhibitors.
Asunto(s)
Antivirales , Farmacorresistencia Viral , Genotipo , Indanos , Tiosemicarbazonas , Antivirales/farmacología , Antivirales/química , Animales , Bovinos , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Indanos/farmacología , Indanos/química , Farmacorresistencia Viral/genética , Virus de la Diarrea Viral Bovina Tipo 1/efectos de los fármacos , Virus de la Diarrea Viral Bovina Tipo 1/genética , Virus de la Diarrea Viral Bovina/efectos de los fármacos , Virus de la Diarrea Viral Bovina/genética , Línea Celular , ARN Polimerasa Dependiente del ARN/genética , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Virus de la Diarrea Viral Bovina Tipo 2/genética , Virus de la Diarrea Viral Bovina Tipo 2/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Mutación , ARN Viral/genéticaRESUMEN
Quite recently we discovered that copper(II) complexes with isomeric morpholine-thiosemicarbazone hybrid ligands show good cytotoxicity in cancer cells and that the molecular target responsible for this activity might be tubulin. In order to obtain better lead drug candidates, we opted to exploit the power of coordination chemistry to (i) assemble structures with globular shape to better fit the colchicine pocket and (ii) vary the metal ion. We report the synthesis and full characterization of bis-ligand cobalt(III) and iron(III) complexes with 6-morpholinomethyl-2-formylpyridine 4N-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL1), 6-morpholinomethyl-2-acetylpyridine 4N-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL2), and 6-morpholinomethyl-2-formylpyridine 4N-phenyl-3-thiosemicarbazone (HL3), and mono-ligand nickel(II), zinc(II) and palladium(II) complexes with HL1, namely [CoIII(HL1)(L1)](NO3)2 (1), [CoIII(HL2)(L2)](NO3)2 (2), [CoIII(HL3)(L3)](NO3)2 (3), [FeIII(L2)2]NO3 (4), [FeIII(HL3)(L3)](NO3)2 (5), [NiII(L1)]Cl (6), [Zn(L1)Cl] (7) and [PdII(HL1)Cl]Cl (8). We discuss the effect of the metal identity and metal complex stoichiometry on in vitro cytotoxicity and antitubulin activity. The high antiproliferative activity of complex 4 correlated well with inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity were supported by experimental results and molecular docking calculations.
Asunto(s)
Colchicina , Complejos de Coordinación , Tubulina (Proteína) , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Colchicina/química , Colchicina/metabolismo , Colchicina/farmacología , Humanos , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/síntesis química , Sitios de Unión , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Polimerizacion , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Estructura Molecular , Proliferación Celular/efectos de los fármacosRESUMEN
We implemented isosteric replacement of sulfur to selenium in a novel thiosemicarbazone (PPTP4c4mT) to create a selenosemicarbazone (PPTP4c4mSe) that demonstrates potentiated anticancer efficacy and selectivity. Their design specifically incorporated cyclohexyl and styryl moieties to sterically inhibit the approach of their Fe(III) complexes to the oxy-myoglobin heme plane. Importantly, in contrast to the Fe(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. Furthermore, PPTP4c4mSe demonstrated more potent antiproliferative activity than the homologous thiosemicarbazone, PPTP4c4mT, with their selectivity being superior or similar, respectively, to the clinically trialed thiosemicarbazone, COTI-2. An advantageous property of the selenosemicarbazone Zn(II) complexes relative to their thiosemicarbazone analogues was their greater transmetalation to Cu(II) complexes in lysosomes. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer.
Asunto(s)
Antineoplásicos , Selenio , Azufre , Tiosemicarbazonas , Zinc , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/síntesis química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Zinc/química , Selenio/química , Selenio/farmacología , Azufre/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Aim: Novel thiazole hybrids were synthesized via thiazolation of 4-phenylthiosemicarbazone (4). Materials & methods: The anticancer activity against the NCI 60 cancer cell line panel. Results: Methyl 2-(2-((1-(naphthalen-2-yl)ethylidene)hydrazineylidene)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (6a) showed significant anticancer activity at 10 µM with a mean growth inhibition (GI) of 51.18%. It showed the highest cytotoxic activity against the ovarian cancer OVCAR-4 with an IC50 of 1.569 ± 0.06 µM. Compound 6a inhibited PI3Kα with IC50 = 0.225 ± 0.01 µM. Moreover, compound 6a revealed a decrease of Akt and mTOR phosphorylation in OVCAR-4 cells. In addition, antibacterial activity showed that compounds 11 and 12 were the most active against Staphylococcus aureus. Conclusion: Compound 6a is a promising molecule that could be a lead candidate for further studies.
Novel naphthalene-azine-thiazole hybrids 5-12 were synthesized via late-stage thiazolation of the corresponding 4-phenylthiosemicarbazone 4. Compound 6a showed significant anticancer activity at single-dose screening and yielded excellent inhibitory activity with a mean GI of 51.18%. Compound 6a showed the highest cytotoxic activity against OVCAR-4 with an IC50 of 1.569 ± 0.06 µM. Moreover, compound 6a exhibited an IC50 of 31.89 ± 1.19 µM against normal ovarian cell line (OCE1) and a selectivity index of 19.1. Compound 6a inhibited PI3Kα with IC50 = 0.225 ± 0.01 µM compared with alpelisib (IC50 = 0.061 ± 0.003 µM). Moreover, compound 6a revealed a powerful decrease of Akt and mTOR phosphorylation in the OVCAR-4 cell line. The cell cycle analysis showed that compound 6a caused an arrest at the G2/M phase. The compound also increased the total apoptosis by 26.8-fold and raised the level of caspase-3 by 4.34 times in OVCAR-4. In addition, antibacterial activity was estimated against Gram-positive and Gram-negative bacterial strains. Compounds 11 and 12 were the most active derivatives, with MIC value of 256 µg/ml against Staphylococcus aureus. Molecular docking was done and showed that 6a interlocked and fitted well into the ATP binding site of PI3Kα kinase (Protein Data Bank ID: 4JPS) with a fitness value (-119.153 kcal/mol) and forms the key H-bonds with Val851 and Ser854 like the marketed PI3Kα inhibitor alpelisib. Consequently, 6a is the most promising molecule that could be a lead candidate for further studies.
Asunto(s)
Antineoplásicos , Simulación del Acoplamiento Molecular , Staphylococcus aureus , Tiazoles , Tiosemicarbazonas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/síntesis química , Staphylococcus aureus/efectos de los fármacos , Línea Celular Tumoral , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Proliferación Celular/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , SemicarbazonasRESUMEN
Pyridoxal-S-methyl-isothiosemicarbazone (PLITSC) is a member of an important group of ligands characterized by different complexation modes to various transition metals. In this contribution, a new complex containing two differently protonated PLITSC ligands ([Fe(PLITSC-H)(PLITSC)]SO4)â2.5H2O was obtained. The crystal structure was solved by the X-ray analysis and used further for the optimization at B3LYP/6-311++G(d,p)(H,C,N,O,S)/def2-TZVP(Fe) level of theory. Changes in the interaction strength and bond distance due to protonation were observed upon examination by the Quantum Theory of Atoms in Molecules. The protein binding affinity of [Fe(PLITSC-H)(PLITSC)]SO4 towards transport proteins (Bovine Serum Albumin (BSA) and Human Serum Albumin (HSA)) was investigated by the spectrofluorimetric titration and molecular docking. The interactions with the active pocket containing fluorescent amino acids were examined in detail, which explained the fluorescence quenching. The interactions between complex and DNA were followed by the ethidium-bromide displacement titration and molecular docking. The binding along the minor groove was the dominant process involving complex in the proximity of DNA.
Asunto(s)
ADN , Simulación del Acoplamiento Molecular , Unión Proteica , Albúmina Sérica Bovina , Ligandos , ADN/química , ADN/metabolismo , Humanos , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Cristalografía por Rayos X , Tiosemicarbazonas/química , Tiosemicarbazonas/metabolismo , Bovinos , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Animales , Protones , Compuestos Férricos/química , Albúmina Sérica Humana/química , Albúmina Sérica Humana/metabolismo , Sitios de Unión , Hierro/química , Hierro/metabolismoRESUMEN
Currently, there are many uses of metal complexes, especially in the fields of medicinal chemistry and catalysis. Thus, fabrication of new complexes which perform as a catalyst and chemotherapeutic drug is always a beneficial addition to the literature. Herein, we report three heterocyclic thiosemicarbazone-based Pd(II) complexes [Pd(HL1)Cl] (C1), [Pd(L2)(PPh3)] (C2) and [Pd(L3)(PPh3)]Cl (C3) having coligands Cl and PPh3. Thiosemicarbazone ligands (H2L1, H2L2 and HL3) and the complexes (C1-C3) were characterized methodically using several spectroscopic techniques. Single-crystal X-ray diffraction methods reveal that the structural environment around the metal center of C2 is square planar, while for C1 and C3 it is a slighty distorted square plane. The supramolecular network of compounds was built via hydrogen bonds, C-Hâ¯π and πâ¯π interactions. Density functional theory (DFT) study of the structure of the complexes supports experimental findings. The application of these complexes as catalysts toward Suzuki-Miyaura coupling reactions has been examined with various aryl halides and phenyl boronic acid in PEG 400 solvent. The complexes displayed good biomolecular interactions with DNA/protein, with a binding constant value of the order of 105 M-1. C3 showed greater binding efficacy toward these biomolecules than the other complexes, which might be due to the cationic nature of C3. Furthermore, antitumor activity of the complexes was studied against the human triple-negative breast cancer (TNBC) cell line MDA-MB-231. It was found that C3 was more toxic (IC50 = 10 ± 2.90 µM) toward MDA-MB-231 cells than the other complexes. A known chemotherapeutic drug, 5-fluorouracil, was included as positive control. The programmed cell death mechanism of C3 was confirmed. Additionally, complex-induced apoptosis was confirmed and occurred via a mitochondria-dependent (intrinsic) pathway.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Paladio , Tiosemicarbazonas , Paladio/química , Paladio/farmacología , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Catálisis , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Teoría Funcional de la Densidad , Modelos Moleculares , Apoptosis/efectos de los fármacosRESUMEN
Copper complexes have shown promising anticancer properties, but they are often poorly soluble in aqueous solutions, thus limiting their possible medical developments and applications. We have recently isolated some copper(II) complexes with salicylaldehyde thiosemicarbazone ligands exhibiting remarkable nanomolar cytotoxic activity, but in vivo tests evidenced several difficulties related to their poor solubility. To overcome these limitations and increase solubility in aqueous solution, herein we report the synthetic strategy that led to the introduction of the sulfonic group on the ligands, then separated as salts (NaH2L1 - NaH2L5), as well as the synthesis and characterization of the related copper(II) complexes. The characterization of the complexes is completed by the analysis of the structures obtained by X-rays diffraction on single crystals on the species [Cu(HL5)(H2O)]2.2H2O, [Cu(HL2)(H2O)2].2H2O, and [Cu(HL1)(H2O]2.2H2O. While the uncoordinated ligands do not affect cancer cell viability, copper(II) complexes exhibit low to sub-micromolar cytotoxic activity, which is maintained in 3D (HCT-15 and 2008) spheroidal models of cancer cell. Notably, copper(II) complexes were selective towards cancer cells, showing high selectivity indexes. Investigations focused on elucidating the mechanism of action evidenced the protein disulfide-isomerase as an innovative molecular target for this class of water-soluble copper(II) complexes. Finally, preliminary in vivo experiments performed with the most representative derivative in the murine Lewis Lung Carcinoma, highlight its significant antitumor efficacy and better tolerability profile with respect to the reference metallodrug, suggesting for this sulfonated Cu(II) complex a potential clinical relevance.
Asunto(s)
Antineoplásicos , Cobre , Ensayos de Selección de Medicamentos Antitumorales , Proteína Disulfuro Isomerasas , Solubilidad , Tiosemicarbazonas , Agua , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Humanos , Agua/química , Animales , Cobre/química , Cobre/farmacología , Ratones , Proteína Disulfuro Isomerasas/antagonistas & inhibidores , Proteína Disulfuro Isomerasas/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proliferación Celular/efectos de los fármacos , Línea Celular TumoralRESUMEN
The reaction mechanism of tthe formation of azomethine ylides from isatins and sarcosine is addressed in the literature in a general manner. This computational study aims to explore the mechanistic steps for this reaction in detail and to assess the reactivity of formed ylide in a 1,3-dipolar cycloaddition reaction with 7-oxabenzonorbornadiene. For this purpose, density functional theory (DFT) calculations at the M06-2X(SMD,EtOH)/6-31G(d,p) level were employed. The results indicate that CO2 elimination is the rate-determining step, the activation barrier for 1,3-dipolar cycloaddition is lower, and the formed ylide will readily react with dipolarophiles. The substitution of isatine with electron-withdrawal groups slightly decreases the activation barrier for ylide formation.
Asunto(s)
Compuestos Azo , Reacción de Cicloadición , Sarcosina , Tiosemicarbazonas , Tiosemicarbazonas/química , Compuestos Azo/química , Sarcosina/química , Sarcosina/análogos & derivados , Isatina/química , Modelos Moleculares , Teoría Funcional de la Densidad , Norbornanos/química , Estructura MolecularRESUMEN
1H-indole-2,3-dione 3-[4-(4-sulfamoylphenyl)thiosemicarbazones] (6a-j) were evaluated against Para-influenza-3, Reovirus-1, Sindbis, Coxsackie B4 and Punto Toro viruses. New 1-methyl-1H-indole-2,3-dione 3-[4-(4-sulfamoylphenyl)thiosemicarbazones] (7a-c) were synthesized to evaluate the contribution of methyl substitution at position 1- of the indole ring to antiviral activity. The test results showed that compounds 5-trifluoromethoxy- substituted 6c (EC50: 2-9 µM) and 5-bromo- substituted 6f (EC50: 2-3 µM) have non-toxic selective antiviral activity while not all standards are active against Reovirus-1. Molecular docking studies of 6c and 6f were carried out to determine the possible binding positions with Reovirus-1. Trifluoromethoxy and bromine substitutions at position 5- of the indole ring provided selective antiviral activity, while methyl substitution at position 1- of the indole ring significantly decreased the activity and increased toxicity against Reovirus-1.
Asunto(s)
Antivirales , Tiosemicarbazonas , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/síntesis química , Simulación del Acoplamiento Molecular , Animales , Indoles/farmacología , Indoles/química , Humanos , Relación Estructura-ActividadRESUMEN
Cancer is a complex and multifactorial disease characterized by uncontrolled cell growth and is one of the main causes of death in the world. This work aimed to evaluate a small series of 10 different indole-thiosemicarbazone compounds as potential antitumor agents. This is a pioneering study. For this, the antioxidant and cytotoxic capacity against normal and tumor cells was evaluated. The results showed that the compounds were able to promote moderate to low antioxidant activity for the ABTS radical scavenging assay. ADMET in silico assays showed that the compounds exhibited good oral bioavailability. As for toxicity, they were able to promote low cytotoxicity against normal cells, in addition to not being hemolytic. The compounds showed promising in vitro antitumor activity against the T47D, MCF-7, Jurkat and DU-145 strains, not being able to inhibit the growth of the Hepg2 strain. Through this in vitro study, it can be concluded that the compounds are potential candidates for antitumor agents.
Asunto(s)
Antineoplásicos , Antioxidantes , Indoles , Tiosemicarbazonas , Humanos , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Indoles/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antioxidantes/farmacología , Línea Celular Tumoral , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacosRESUMEN
Most breast and prostate cancers are caused by abnormal production or action of steroidal hormones. Hormonal drugs based on steroid scaffolds represent a significant class of chemotherapeutics that are routinely used in chemotherapy. In this study, the synthesis of new 17a-homo lactone and 17α-(pyridine-2-ylmethyl) androstane derivatives with hydrazide and semicarbazone motifs is presented. All compounds were screened for their effect on cell viability against a panel of five cancer cell lines and one healthy cell line. Two compounds showed significant cytotoxicity against cancer cells, with low toxicity against healthy cells. The relative binding affinities of compounds for the ligand-binding domains of estrogen receptor α, estrogen receptor ß, androgen receptor and glucocorticoid receptor were tested using a fluorescence screen in yeast. Potential for inhibition of aldo-keto reductase 1C3 and 1C4 activity was measured in vitro. Experimental results are analyzed in the context of molecular docking simulations. Our results could help guide design of steroid compounds with improved anticancer properties against androgen- and estrogen-dependent cancers.
Asunto(s)
Antineoplásicos , Simulación del Acoplamiento Molecular , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Hidrazinas/farmacología , Hidrazinas/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Esteroides/química , Esteroides/farmacología , Semicarbazonas/farmacología , Semicarbazonas/química , Semicarbazonas/síntesis química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
The development of copper(II) thiosemicarbazone complexes as potential anticancer agents, possessing dual functionality as inhibitors of R2 ribonucleotide reductase (RNR) and tubulin polymerization by binding at the colchicine site, presents a promising avenue for enhancing therapeutic effectiveness. Herein, we describe the syntheses and physicochemical characterization of four isomeric proligands H2L3-H2L6, with the methylmorpholine substituent at pertinent positions of the pyridine ring, along with their corresponding Cu(II) complexes 3-6. Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the in vitro antiproliferative activity in human uterine sarcoma MES-SA cells and the multidrug-resistant derivative MES-SA/Dx5 cells. Activity correlated strongly with quenching of the tyrosyl radical (Yâ¢) of mouse R2 RNR protein, inhibition of RNR activity in the cancer cells, and inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity, supported by experimental results and molecular modeling calculations, are presented.
Asunto(s)
Antineoplásicos , Cobre , Morfolinas , Ribonucleótido Reductasas , Tiosemicarbazonas , Tubulina (Proteína) , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/síntesis química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ribonucleótido Reductasas/antagonistas & inhibidores , Ribonucleótido Reductasas/metabolismo , Tubulina (Proteína)/metabolismo , Animales , Morfolinas/farmacología , Morfolinas/química , Morfolinas/síntesis química , Cobre/química , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Polimerizacion/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Ensayos de Selección de Medicamentos Antitumorales , Modelos MolecularesRESUMEN
A new pyrazole based thiosemicarbazone ligand, 5-methyl-3-formylpyrazole-N(4)-isopropylthiosemicarbazone, (HMPzNHPri) (compound I), and its cobalt(III) and nickel(II) complexes, [Co(MPzNHPri)2]Cl (compound II) and [Ni(HMPzNHPri)2]Br2 (compound III), respectively, have been synthesized and characterized through various physico-chemical and spectroscopic studies. Both the reported Co(III) and Ni(II) complexes are cationic in nature and behave as 1:1 and 1:2 electrolytes in MeOH, respectively. Electronic spectral features of the complexes have classified them as distorted octahedral ones. IR spectral data (4000-450 cm-1) have suggested a monoprotic tridentate (NNS) function of compound I coordinating to the Co(III) ion via the pyrazolyl (tertiary) ring nitrogen, azomethine nitrogen and thiolato sulphur atom; while for compound III, compound I has been found to act as neutral NNS tridentate one, coordinating to Ni(II) via the pyrazolyl iminic nitrogen, azomethine nitrogen and thioketo sulphur. Structural features of all the compounds are confirmed by the single crystal X-ray data. All the compounds reported here have been found to exhibit significant photocatalytic activity towards degradation of Methylene Blue (MB) under UV radiation. Anticancer activity of all the three compounds against cancer cell lines (HeLa and A549) and a normal cell line (HEK293) have been investigated. Compound II has been found to be more efficient against the human cervical cancer cell (HeLa) and the lung cancer cell (A549) than compounds I and III. The ligand and both the complexes display potential activities against both gram-positive (Bacillus subtilis MTCC 7193) and gram-negative bacteria (E. coli MTCC 1610).
Asunto(s)
Antineoplásicos , Cobalto , Complejos de Coordinación , Níquel , Pirazoles , Tiosemicarbazonas , Tiosemicarbazonas/química , Níquel/química , Cobalto/química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Humanos , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X/métodos , Ligandos , Línea Celular Tumoral , Catálisis , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Pruebas de Sensibilidad MicrobianaRESUMEN
Induction of cuproptosis and targeting of multiple signaling pathways show promising applications in tumor therapy. In this study, we synthesized two thiosemicarbazone-copper complexes ([CuII(L)Cl] 1 and [CuII2CuI(L)2Cl3] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand), to assess their antilung cancer activities. Both copper complexes showed better anticancer activity than cisplatin and exhibited hemolysis comparable to that of cisplatin. In vivo experiments showed that complex 2 retarded the A549 cell growth in a mouse xenograft model with low systemic toxicity. Primarily, complex 2 kills lung cancer cells in vitro and in vivo by triggering multiple pathways, including cuproptosis. Complex 2 is the first mixed-valent Cu(I/II) complex to induce cellular events consistent with cuproptosis in cancer cells, which may stimulate the development of mixed-valent copper complexes and provide effective cancer therapy.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Cobre , Neoplasias Pulmonares , Tiosemicarbazonas , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/uso terapéutico , Humanos , Cobre/química , Animales , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/uso terapéutico , Ratones , Ratones Desnudos , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Línea Celular Tumoral , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Células A549 , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Hemólisis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ratones Endogámicos BALB CRESUMEN
Thiosemicarbazones are promising classes of compounds with antitumor activity. For this study, six 2,4-dihydroxy-benzylidene-thiosemicarbazones compounds were synthesized. These compounds were submitted to different assays in silico, in vitro and in vivo to evaluate the toxicological, antioxidant and antitumor effects. The in silico results were evaluated by the SwissADME and pkCSM platforms and showed that all compounds had good oral bioavailability profiles. The in vitro and in vivo toxicity assays showed that the compounds showed low cytotoxicity against different normal cells and did not promote hemolytic effects. The single dose acute toxicity test (2000 mg/kg) showed that none of the compounds were toxic to mice. In in vitro antioxidant activity assays, the compounds showed moderate to low activity, with PB17 standing out for the ABTS radical capture assay. The in vivo antioxidant activity highlighted the compounds 1, 6 and 8 that promoted a significant increase in the concentration of liver antioxidant enzymes. Finally, all compounds showed promising antitumor activity against different cell lines, especially MCF-7 and DU145 lines, in addition, they inhibited the growth of sarcoma 180 at concentrations lower than 50 mg/kg. These results showed that the evaluated compounds can be considered as potential antitumor agents.
Asunto(s)
Antineoplásicos , Antioxidantes , Tiosemicarbazonas , Animales , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Antineoplásicos/farmacología , Antioxidantes/farmacología , Ratones , Humanos , Masculino , Línea Celular Tumoral , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Compuestos de Bencilideno/farmacología , Compuestos de Bencilideno/químicaRESUMEN
The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K2PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2CO3. In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy.
Asunto(s)
Antineoplásicos , Apoptosis , Neoplasias de la Mama , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Tiosemicarbazonas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Apoptosis/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Femenino , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Platino (Metal)/química , Platino (Metal)/farmacología , Autofagia/efectos de los fármacosRESUMEN
Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 µM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 µM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.
Asunto(s)
Cromonas , Diabetes Mellitus Tipo 2 , Diseño de Fármacos , Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes , Simulación del Acoplamiento Molecular , Tiosemicarbazonas , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Cromonas/farmacología , Cromonas/síntesis química , Cromonas/química , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismo , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estructura Molecular , Humanos , Simulación de Dinámica Molecular , Simulación por Computador , Relación Dosis-Respuesta a DrogaRESUMEN
Macrozones are novel conjugates of azithromycin and thiosemicarbazones, which exhibit very good in vitro antibacterial activities against susceptible and some resistant bacterial strains thus showing a potential for further development. A combination of spectrometric (fluorimetry, STD and WaterLOGSY NMR) and molecular docking studies provided insights into atomic details of interactions between selected macrozones and biological receptors such as E. coli ribosome and bovine serum albumin. Fluorimetric measurements revealed binding constants in the micro-molar range while NMR experiments provided data on binding epitopes. It has been demonstrated that both STD and WaterLOGSY gave comparable and consistent results unveiling atoms in intimate contacts with biological receptors. Docking studies pointed towards main interactions between macrozones and E. coli ribosome which included specific π - π stacking and hydrogen bonding interactions with thiosemicarbazone part extending down the ribosome exit tunnel. The results of the docking experiments were in fine correlation with those obtained by NMR and fluorimetry. Our investigation pointed towards a two-site binding mechanism of interactions between macrozones and E. coli ribosome which is the most probable reason for their activity against azithromycin-resistant strains. Much better activity of macrozone-nickel coordinated compound against E. coli ribosome compared to other macrozones has been attributed to the higher polarity which enabled better bacterial membrane penetration and binding of the two thiosemicarbazone units thus additionally contributing to the overall binding energy. The knowledge gained in this study should play an important role in anti-infective macrolide design in the future.
Asunto(s)
Antibacterianos , Escherichia coli , Fluorometría , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Antibacterianos/farmacología , Antibacterianos/química , Escherichia coli/efectos de los fármacos , Sitios de Unión , Estructura Molecular , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Relación Estructura-Actividad , Ribosomas/metabolismo , Ribosomas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Animales , Bovinos , Azitromicina/farmacología , Azitromicina/química , Azitromicina/metabolismoRESUMEN
An extensive range of new biologically active morpholine based thiosemicarbazones derivatives 3a-r were synthesized, characterized by spectral techniques and evaluated as inhibitors of ENPP isozymes. Most of the novel thiosemicarbazones exhibit potent inhibition towards NPP1 and NPP3 isozymes. Compound 3â¯h was potent inhibitor of NPP1 with IC50 value of 0.55⯱â¯0.02. However, the most powerful inhibitor of NPP3 was 3e with an IC50 value of 0.24⯱â¯0.02. Furthermore, Lineweaver-Burk plot for compound 3â¯h against NPP1 and for compound 3e against NPP3 was devised through enzymes kinetics studies. Molecular docking and in silico studies was also done for analysis of interaction pattern of all newly synthesized compounds. The results were further validated by molecular dynamic (MD) simulation where the stability of conformational transformation of the best protein-ligand complex (3e) were justified on the basis of RMSD and RMSF analysis.
Asunto(s)
Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Morfolinas , Hidrolasas Diéster Fosfóricas , Pirofosfatasas , Tiosemicarbazonas , Morfolinas/química , Morfolinas/farmacología , Morfolinas/síntesis química , Hidrolasas Diéster Fosfóricas/química , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/antagonistas & inhibidores , Pirofosfatasas/química , Pirofosfatasas/metabolismo , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/síntesis química , Humanos , Cinética , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/síntesis química , Simulación por Computador , Relación Estructura-Actividad , LigandosRESUMEN
Reactions between sodium tetrachloropalladate and 2- (or 4-) substituted 4-phenyl-3-thiosemicarbazone ligands (HLR), with various electron-donating and electron-withdrawing substituents (R = OCH3, NO2, and Cl), afford square-planar complexes of the general formula [Pd(LR)2]. Ground-state geometry optimization and the vibrational analysis of cis- and trans-isomers of the complexes were carried out to get an insight into the stereochemistry of the complexes. Natural bond orbital analysis was used to analyze how the nature of the substituent affects the natural charge of the metal center, the type of hybridization, and the strength of the M-N and M-S bonds. Using spectrophotometry, the stability of the complexes, and their DNA binding abilities were assessed. The Pd(II) complexes showed moderate cytotoxicity against MCF-7 and Caco-2â cell lines, two of the assessed malignant cell lines, resulting in all known cell death types, including early apoptotic bodies and late apoptotic vacuoles as well as evident necrotic bodies.