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1.
BMC Vet Res ; 20(1): 196, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38741109

RESUMEN

BACKGROUND: Hypoxia is a detrimental factor in solid tumors, leading to aggressiveness and therapy resistance. OMX, a tunable oxygen carrier from the heme nitric oxide/oxygen-binding (H-NOX) protein family, has the potential to reduce tumor hypoxia. [18F]Fluoromisonidazole ([18F]FMISO) positron emission tomography (PET) is the most widely used and investigated method for non-invasive imaging of tumor hypoxia. In this study, we used [18F]FMISO PET/CT (computed tomography) to assess the effect of OMX on tumor hypoxia in spontaneous canine tumors. RESULTS: Thirteen canine patients with various tumors (n = 14) were randomly divided into blocks of two, with the treatment groups alternating between receiving intratumoral (IT) OMX injection (OMX IT group) and intravenous (IV) OMX injection (OMX IV group). Tumors were regarded as hypoxic if maximum tumor-to-muscle ratio (TMRmax) was greater than 1.4. In addition, hypoxic volume (HV) was defined as the region with tumor-to-muscle ratio greater than 1.4 on [18F]FMISO PET images. Hypoxia was detected in 6/7 tumors in the OMX IT group and 5/7 tumors in the OMX IV injection group. Although there was no significant difference in baseline hypoxia between the OMX IT and IV groups, the two groups showed different responses to OMX. In the OMX IV group, hypoxic tumors (n = 5) exhibited significant reductions in tumor hypoxia, as indicated by decreased TMRmax and HV in [18F]FMISO PET imaging after treatment. In contrast, hypoxic tumors in the OMX IT group (n = 6) displayed a significant increase in [18F]FMISO uptake and variable changes in TMRmax and HV. CONCLUSIONS: [18F]FMISO PET/CT imaging presents a promising non-invasive procedure for monitoring tumor hypoxia and assessing the efficacy of hypoxia-modulating therapies in canine patients. OMX has shown promising outcomes in reducing tumor hypoxia, especially when administered intravenously, as evident from reductions in both TMRmax and HV in [18F]FMISO PET imaging.


Asunto(s)
Enfermedades de los Perros , Misonidazol , Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Hipoxia Tumoral , Animales , Perros , Misonidazol/análogos & derivados , Tomografía Computarizada por Tomografía de Emisión de Positrones/veterinaria , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Enfermedades de los Perros/diagnóstico por imagen , Enfermedades de los Perros/tratamiento farmacológico , Femenino , Hipoxia Tumoral/efectos de los fármacos , Masculino , Neoplasias/veterinaria , Neoplasias/tratamiento farmacológico , Neoplasias/diagnóstico por imagen , Tiosemicarbazonas/uso terapéutico , Tiosemicarbazonas/farmacología , Complejos de Coordinación
2.
Bioorg Chem ; 147: 107338, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38583253

RESUMEN

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/metabolismo
3.
J Med Chem ; 67(7): 5744-5757, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38553427

RESUMEN

To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed a copper (Cu) compound based on the properties of the human serum albumin (HSA)-indomethacin (IND) complex to remodel the tumor microenvironment (TME). We optimized a series of Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds to obtain a Cu(II) compound (C4) with significant cytotoxicity and then constructed an HSA-IND-C4 complex (HSA-IND-C4) delivery system. IND and C4 bind to the hydrophobic cavities of the IB and IIA domains of HSA, respectively. In vivo, the HSA-IND-C4 not only showed enhanced antitumor efficacy relative to C4 and C4 + IND but also improved their targeting ability and decreased their side effects. The antitumor mechanism of C4 + IND involved acting on the different components of the TME. IND inhibited tumor-related inflammation, while C4 not only induced apoptosis and autophagy of cancer cells but also inhibited tumor angiogenesis.


Asunto(s)
Antineoplásicos , Neoplasias , Profármacos , Tiosemicarbazonas , Humanos , Albúmina Sérica Humana/química , Cobre/química , Albúmina Sérica/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/uso terapéutico , Indometacina/uso terapéutico , Microambiente Tumoral , Profármacos/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Neoplasias/tratamiento farmacológico
4.
Chem Biodivers ; 21(5): e202400363, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38470083

RESUMEN

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-2 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.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Paladio , Tiosemicarbazonas , Humanos , Paladio/química , Paladio/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Ligandos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Células MCF-7 , Estructura Molecular , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Relación Estructura-Actividad , ADN/química , ADN/metabolismo , ADN/efectos de los fármacos
5.
Mol Pharm ; 21(4): 1987-1997, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38507593

RESUMEN

The misuse and overdose of antimicrobial medicines are fostering the emergence of novel drug-resistant pathogens, providing negative repercussions not only on the global healthcare system due to the rise of long-term or chronic patients and inefficient therapies but also on the world trade, productivity, and, in short, to the global economic growth. In view of these scenarios, novel action plans to constrain this antibacterial resistance are needed. Thus, given the proven antiproliferative tumoral and microbial features of thiosemicarbazone (TSCN) ligands, we have here synthesized a novel effective antibacterial copper-thiosemicarbazone complex, demonstrating both its solubility profile and complex stability under physiological conditions, along with their safety and antibacterial activity in contact with human cellular nature and two most predominant bacterial strains, respectively. A significant growth inhibition (17% after 20 h) is evidenced over time, paving the way toward an effective antibacterial therapy based on these copper-TSCN complexes.


Asunto(s)
Antiinfecciosos , Complejos de Coordinación , Compuestos Organometálicos , Tiosemicarbazonas , Humanos , Cobre/farmacología , Tiosemicarbazonas/farmacología , Antiinfecciosos/farmacología , Antibacterianos/farmacología , Complejos de Coordinación/farmacología
6.
ACS Chem Neurosci ; 15(7): 1432-1455, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38477556

RESUMEN

Alzheimer's disease (AD) is the most prevalent cause of dementia characterized by a progressive cognitive decline. Addressing neuroinflammation represents a promising therapeutic avenue to treat AD; however, the development of effective antineuroinflammatory compounds is often hindered by their limited blood-brain barrier (BBB) permeability. Consequently, there is an urgent need for accurate, preclinical AD patient-specific BBB models to facilitate the early identification of immunomodulatory drugs capable of efficiently crossing the human AD BBB. This study presents a unique approach to BBB drug permeability screening as it utilizes the familial AD patient-derived induced brain endothelial-like cell (iBEC)-based model, which exhibits increased disease relevance and serves as an improved BBB drug permeability assessment tool when compared to traditionally employed in vitro models. To demonstrate its utility as a small molecule drug candidate screening platform, we investigated the effects of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(atsm)) and a library of metal bis(thiosemicarbazone) complexes─a class of compounds exhibiting antineuroinflammatory therapeutic potential in neurodegenerative disorders. By evaluating the toxicity, cellular accumulation, and permeability of those compounds in the AD patient-derived iBEC, we have identified 3,4-hexanedione bis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(dtsm)) as a candidate with good transport across the AD BBB. Furthermore, we have developed a multiplex approach where AD patient-derived iBEC were combined with immune modulators TNFα and IFNγ to establish an in vitro model representing the characteristic neuroinflammatory phenotype at the patient's BBB. Here, we observed that treatment with CuII(dtsm) not only reduced the expression of proinflammatory cytokine genes but also reversed the detrimental effects of TNFα and IFNγ on the integrity and function of the AD iBEC monolayer. This suggests a novel pathway through which copper bis(thiosemicarbazone) complexes may exert neurotherapeutic effects on AD by mitigating BBB neuroinflammation and related BBB integrity impairment. Together, the presented model provides an effective and easily scalable in vitro BBB platform for screening AD drug candidates. Its improved translational potential makes it a valuable tool for advancing the development of metal-based compounds aimed at modulating neuroinflammation in AD.


Asunto(s)
Enfermedad de Alzheimer , Tiosemicarbazonas , Humanos , Barrera Hematoencefálica/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Cobre/metabolismo , Enfermedades Neuroinflamatorias , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/metabolismo , Tiosemicarbazonas/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo
7.
Turkiye Parazitol Derg ; 48(1): 39-44, 2024 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-38449366

RESUMEN

Objective: A series of aromatic thiosemicarbazone-oxime [TP1 and TP2] derivatives and their Ni(II), Cu(II), and Co(II) complexes were synthesized, and their larvicidal activity was evaluated against Aedes aegypti and Aedes albopictus larvae. The efficacy of these substances to Aedes albopictus larvae has been demonstrated for the first time. Methods: Laboratory colonized Aedes aegypti and Aedes albopictus larvae were subjected to larvicidal activity tests. Larval mortality rates at 24 and 48 hours were recorded and LC50 values were calculated. The study was carried out at Aydin Adnan Menderes University in 2021. Results: For Aedes aegypti, LC50 of TP1 and its Co(II) complex were 15.41, 9.75, µg/mL whereas for TP2 and its Co(II) complex, LC50 were 21.62, 20.50 µg/mL after 24 and 48 h respectively. For Aedes albopictus, TP1 and its Co(II) complex showed an LC50 of 12.06, 8.75 µg/mL, whereas TP2 and its Co(II) complex showed an LC50 of 32.87, 25.48 µg/mL, for 24, and 48 h respectively. Conclusion: Both TP1 and TP2 compounds and their Co(II) complexes presented high efficacy against the larvae; it can be said that C=S groups in thiosemicarbazone derivatives are effective in showing activity and for this reason, studies should be continued to make these components effective.


Asunto(s)
Aedes , Complejos de Coordinación , Tiosemicarbazonas , Humanos , Animales , Larva , Tiosemicarbazonas/farmacología
8.
Int J Biol Macromol ; 266(Pt 2): 131068, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38531526

RESUMEN

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 3 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 3 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 , Ligandos
9.
J Med Chem ; 67(5): 3843-3859, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38442035

RESUMEN

To develop a potential theranostic metal agent to reverse the resistance of cancer cells to cisplatin and effectively inhibit tumor growth and metastasis, we proposed to design a cyclometalated iridium (Ir) complex based on the properties of the tumor environment (TME). To the end, we designed and synthesized a series of Ir(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes by modifying the hydrogen atom(s) of the N-3 position of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds and the structure of cyclometalated Ir(III) dimers and then investigated their structure-activity and structure-fluorescence relationships to obtain an Ir(III) complex (Ir5) with remarkable fluorescence and cytotoxicity to cancer cells. Ir5 not only possesses mitochondria-targeted properties but also overcomes cisplatin resistance and effectively inhibits tumor growth and metastasis in vivo. Besides, we confirmed the anticancer mechanisms of Ir5 acting on different components in the TME: directly killing liver cancer cells by inducing necroptosis and activating the necroptosis-related immune response.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Naftalenos , Neoplasias , Tiosemicarbazonas , Humanos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Antineoplásicos/química , Iridio/farmacología , Iridio/química , Medicina de Precisión , Necroptosis , Neoplasias/tratamiento farmacológico , Mitocondrias , Complejos de Coordinación/química , Línea Celular Tumoral
10.
Sci Rep ; 14(1): 5929, 2024 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-38467696

RESUMEN

The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Complejos de Coordinación , Enfermedades Neurodegenerativas , Tiosemicarbazonas , Humanos , Ratones , Animales , Cobre/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Ratones Transgénicos , Médula Espinal/metabolismo , Ceruloplasmina/metabolismo , Modelos Animales de Enfermedad
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 313: 124117, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38461559

RESUMEN

Cancer's global impact necessitates innovative and less toxic treatments. Thiosemicarbazones (TSCs), adaptable metal chelators, offer such potential. In this study, we have synthesized N (4)-substituted heterocyclic TSCs from syringaldehyde (TSL1, TSL2), and also report the unexpected copper-mediated cyclization of the TSCs to form thiadiazoles (TSL3, TSL4), expanding research avenues. This work includes extensive characterization and studies such as DNA/protein binding, molecular docking, and theoretical analyses to demonstrate the potential of the as-prepared TSCs and thiadiazoles against different cancer cells. The DFT results depict that the thiadiazoles exhibit greater structural stability and reduced reactivity compared to the corresponding TSCs. The docking results suggest superior EGFR inhibition for TSL3 with a binding constant value of - 6.99 Kcal/mol. According to molecular dynamics studies, the TSL3-EGFR complex exhibits a lower average RMSD (1.39 nm) as compared to the TSL1-EGFR complex (3.29 nm) suggesting that both the thiadiazole and thiosemicarbazone examined here can be good inhibitors of EGFR protein, also that TSL3 can inhibit EGFR better than TSL1. ADME analysis indicates drug-likeness and oral availability of the thiadiazole-based drugs. The DNA binding experiment through absorption and emission spectroscopy discovered that TSL3 is more active towards DNA which is quantitatively calculated with a Kb value of 4.74 × 106 M-1, Kq value of 4.04 × 104 M-1and Kapp value of 5 × 106 M-1. Furthermore, the BSA binding studies carried out with fluorescence spectroscopy showed that TSL3 shows better binding capacity (1.64 × 105 M-1) with BSA protein. All the compounds show significant cytotoxicity against A459-lung, MCF-7-breast, and HepG2-liver cancer cell lines; TSL3 exhibits the best cytotoxicity, albeit less effective than cisplatin. Thiadiazoles demonstrate greater cytotoxicity than the TSCs. Overall, the promise of TSCs and thiadiazoles in cancer research is highlighted by this study. Furthermore, it unveils unexpected copper-mediated cyclization of the TSCs to thiadiazoles.


Asunto(s)
Antineoplásicos , Tiadiazoles , Tiosemicarbazonas , Simulación del Acoplamiento Molecular , Teoría Funcional de la Densidad , Cobre/farmacología , Cobre/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Ciclización , Tiadiazoles/farmacología , Tiadiazoles/química , Espectrometría de Fluorescencia , ADN/química , Receptores ErbB/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química
12.
Chemistry ; 30(21): e202304212, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38408264

RESUMEN

Cu-thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials. Copper(II)-di-2-pyridylketone-4,4-dimethyl-thiosemicarbazone (CuII-Dp44mT) showed anticancer activity in the submicromolar concentration range in cell culture. The interaction of CuII-Dp44mT with thiols leading to their depletion or inhibition was proposed to be involved in this activity. Indeed, CuII-Dp44mT can catalyze the oxidation of thiols although with slow kinetics. The present work aims to obtain insights into the catalytic activity and selectivity of CuII-Dp44mT toward the oxidation of different biologically relevant thiols. Reduced glutathione (GSH), L-cysteine (Cys), N-acetylcysteine (NAC), D-penicillamine (D-Pen), and the two model proteins glutaredoxin (Grx) and thioredoxin (Trx) were investigated. CuII-Dp44mT catalyzed the oxidation of these thiols with different kinetics, with rates in the following order D-Pen>Cys≫NAC>GSH and Trx>Grx. CuII-Dp44mT was more efficient than CuII chloride for the oxidation of NAC and GSH, but not D-Pen and Cys. In mixtures of biologically relevant concentrations of GSH and either Cys, Trx, or Grx, the oxidation kinetics and spectral properties were similar to that of GSH alone, indicating that the interaction of these thiols with CuII-Dp44mT is dominated by GSH. Hence GSH could protect other thiols against potential deleterious oxidation by CuII-Dp44mT.


Asunto(s)
Cobre , Tiosemicarbazonas , Cobre/metabolismo , Compuestos de Sulfhidrilo , Oxidación-Reducción , Glutatión/metabolismo , Penicilamina/metabolismo , Acetilcisteína/metabolismo
13.
Virology ; 593: 110014, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38401340

RESUMEN

African swine fever (ASF) caused by African swine fever virus (ASFV) is a highly infectious and lethal swine disease. Currently, there is only one novel approved vaccine and no antiviral drugs for ASFV. In the study, a high-throughput screening of an FDA-approved drug library was performed to identify several drugs against ASFV infection in primary porcine alveolar macrophages. Triapine and cytarabine hydrochloride were identified as ASFV infection inhibitors in a dose-dependent manner. The two drugs executed their antiviral activity during the replication stage of ASFV. Furthermore, molecular docking studies showed that triapine might interact with the active center Fe2+ in the small subunit of ASFV ribonucleotide reductase while cytarabine hydrochloride metabolite might interact with three residues (Arg589, Lys593, and Lys631) of ASFV DNA polymerase to block new DNA chain extension. Taken together, our results suggest that triapine and cytarabine hydrochloride displayed significant antiviral activity against ASFV in vitro.


Asunto(s)
Virus de la Fiebre Porcina Africana , Fiebre Porcina Africana , Piridinas , Tiosemicarbazonas , Porcinos , Animales , Virus de la Fiebre Porcina Africana/genética , Virus de la Fiebre Porcina Africana/metabolismo , Fiebre Porcina Africana/prevención & control , Simulación del Acoplamiento Molecular , Antivirales/farmacología , Antivirales/metabolismo , Citarabina/metabolismo , Citarabina/farmacología , Replicación Viral
14.
Dalton Trans ; 53(11): 5073-5083, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38375910

RESUMEN

A series of Pd(II) complexes of the general formula [PdX(NNS)] (X = Cl, Br, I, NCS and phenyl-tetrazole-thiolato; NNS = 2-quinolinecarboxyaldehyde-N4-phenylthiosemicarbazone) was tested against four malignant cell lines for their antiproliferative properties and the outcomes were compared to those seen in normal mouse splenocytes. Various auxiliary ligands were substituted in order to investigate the impact of the character of the ligand on the cytotoxicity of this class of Pd(II) complexes. The iodo complex was the most cytotoxic compound towards the Caco-2 cell line in this study. The improved apoptosis and necrosis cell modes were in accordance with the fragmentation results of DNA, which revealed increased fragmentation terminals, especially in isothiocyanate and tetrazole-thiolato complexes. After 24 hours, at half the IC50 of each complex, the complex-treated cells exhibited considerable genotoxicity when compared to the corresponding non-treated control especially in the case of isothiocyanate and tetrazole-thiolato complexes.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Tiosemicarbazonas , Humanos , Animales , Ratones , Línea Celular Tumoral , Tiosemicarbazonas/farmacología , Ligandos , Células CACO-2 , Antineoplásicos/farmacología , Apoptosis , Tetrazoles , Isotiocianatos/farmacología , Complejos de Coordinación/farmacología
15.
Molecules ; 29(2)2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38276575

RESUMEN

The aim of this work is to explore a new library of coordination compounds for medicinal applications. Gallium is known for its various applications in this field. Presently, indium is not particularly important in medicine, but it shares a lot of chemical traits with its above-mentioned lighter companion, gallium, and is also used in radio imaging. These metals are combined with thiosemicarbazones, ligating compounds increasingly known for their biological and pharmaceutical applications. In particular, the few ligands chosen to interact with these hard metal ions share the ideal affinity for a high charge density. Therefore, in this work we describe the synthesis and the characterization of the resulting coordination compounds. The yields of the reactions vary from a minimum of 21% to a maximum of 82%, using a fast and easy procedure. Nuclear Magnetic Resonance (NMR) and Infra Red (IR) spectroscopy, mass spectrometry, elemental analysis, and X-ray Diffraction (XRD) confirm the formation of stable compounds in all cases and a ligand-to-metal 2:1 stoichiometry with both cations. In addition, we further investigated their chemical and biological characteristics, via UV-visible titrations, stability tests, and cytotoxicity and antibiotic assays. The results confirm a strong stability in all explored conditions, which suggests that these compounds are more suitable for radio imaging applications rather than for antitumoral or antimicrobic ones.


Asunto(s)
Complejos de Coordinación , Galio , Tiosemicarbazonas , Galio/farmacología , Galio/química , Indio/química , Tiosemicarbazonas/química , Ligandos , Espectroscopía de Resonancia Magnética , Complejos de Coordinación/química
16.
Front Biosci (Landmark Ed) ; 29(1): 19, 2024 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-38287820

RESUMEN

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy of the skin, and its incidence is increasing annually. Once cSCC becomes metastatic, its associated mortality rate is much higher than that of cSCC in situ. However, the current treatments for progressive cSCC have several limitations. The aim of this study was to suggest a potential compound for future research that may benefit patients with cSCC. METHODS: In this study, we screened the following differentially expressed genes from the Gene Expression Omnibus database: GSE42677, GSE45164, GSE66359, and GSE98767. Using strategies such as protein-protein interaction network analysis and the CYTOSCAPE plugin MCODE, key modules were identified and then verified by Western blotting. Subsequently, related signalling pathways were constituted in the SIGNOR database. Finally, molecular docking analyses and cell viability assay were used to identify a potential candidate drug and verify its growth inhibition ability to A431 cell line. RESULTS: Fifty-one common differentially expressed genes were screened and two key modules were identified. Among them, three core genes were extracted, constituting two signalling pathways, both of which belong to the module associated with mitotic spindles and cell division. A pathway involving CDK1, the TPX2-KIF11 complex, and spindle organization was validated in a series of analyses, including analyses for overall survival, genetic alteration, and molecular structure. Molecular docking analyses identified the pyridine 2-carbaldehyde thiosemicarbazone (NSC689534), which interacts with TPX2 and KIF11, as a potential candidate for the treatment of cSCC. CONCLUSIONS: NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Cutáneas , Tiosemicarbazonas , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Simulación del Acoplamiento Molecular , Transducción de Señal/genética , Regulación Neoplásica de la Expresión Génica
17.
Macromol Rapid Commun ; 45(1): e2300220, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37449343

RESUMEN

Conjugated polymers have received significant attention as potentially lightweight and highly tailorable alternatives to inorganic semiconductors, but their synthesis is often complex, produces toxic byproducts, and they are not typically designed to be degradable or recyclable. These drawbacks necessitate dedicated efforts to discover materials with design motifs that enable targeted and efficient degradation of conjugated polymers. In this vein, the synthetic simplicity of 1,4-dihydropyrrolo[3,2-b]pyrroles (DHPPs) is exploited to access azomethine-containing copolymers via a benign acid-catalyzed polycondensation protocol. Polymerizations involve reacting a dialdehyde-functionalized dihydropyrrolopyrrole with p-phenylenediamine as the comonomer using p-toluenesulfonic acid as a catalyst. The inherent dynamic equilibrium of the azomethine bonds subsequently enabled the degradation of the polymers in solution in the presence of acid. Degradation of the polymers is monitored via NMR, UV-vis absorbance, and fluorescence spectroscopies, and the polymers are shown to be fully degradable. Notably, while absorbance measurements reveal a continued shift to higher energies with extended exposure to acid, fluorescence measurements show a substantial increase in the fluorescence response upon degradation. Results from this study encourage the continued development of environmentally-conscious polymerizations to attain polymeric materials with useful properties while simultaneously creating polymers with structural handles for end-of-life management or/and recyclability.


Asunto(s)
Polímeros , Tiosemicarbazonas , Polímeros/química , Pirroles , Compuestos Azo
18.
Angew Chem Int Ed Engl ; 63(5): e202312663, 2024 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-38032817

RESUMEN

Azomethine imines, as a prominent class of 1,3-dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper- or chiral phosphoric acid catalyzed ring-closure reactions of N'-(2-alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy-induced peripheral neuropathy (CIPN). Remarkably, the (S)- and (R)-atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry.


Asunto(s)
Compuestos Azo , Iminas , Tiosemicarbazonas , Estereoisomerismo , Compuestos Azo/farmacología , Catálisis
19.
J Inorg Biochem ; 251: 112438, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38029536

RESUMEN

Cancer continues to pose a global threat, underscoring the urgent need for more effective and safer treatment options. Gold-based compounds have recently emerged as promising candidates due to their diverse range of biological activities. In this study, three gold(III) complexes derived from thiosemicarbazone ligands have been synthesized, fully characterized, including their X-ray crystal structures. We conducted initial mode-of-action studies on DNA and BSA, followed by a comprehensive investigation into the cytotoxic effects of these novel gold(III) complexes on lung cancer cells (A549, H2052, and H28). The results demonstrated a concentration-dependent cytotoxic response, with H28 cells exhibiting the highest sensitivity to the treatment. Furthermore, the analysis of the cell cycle revealed that these compounds induce cell cycle arrest and promote apoptosis as a response to treatment. We also observed distinct morphological changes and increased oxidative stress, contributing significantly to cell death. Notably, these complexes exhibited the ability to suppress interleukin-6 production in mesothelioma cell lines, and this highlights their anti-inflammatory potential. To gain an initial understanding of cytotoxicity on healthy cells, hemolysis tests were conducted against human blood cells, with no evidence of hemolysis. Furthermore, a toxicity assessment through the in vivo Galleria mellonella model underscored the absence of detectable toxicity. These findings prove that these complexes are promising novel therapeutic agents for lung cancer.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Neoplasias Pulmonares , Tiosemicarbazonas , Humanos , Oro/química , Neoplasias Pulmonares/tratamiento farmacológico , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Hemólisis , Antineoplásicos/farmacología , Antineoplásicos/química , Ligandos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Línea Celular Tumoral
20.
Int Immunopharmacol ; 126: 111259, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37992446

RESUMEN

Multiple studies in the literature have demonstrated that synthetic compounds containing heterocyclic rings possess a reparative potential against acute and chronic inflammation. In the present study, two novel thiosemicarbazone derivatives based on l-ethyl-6-(thiophen-2-yl)indoline-2,3-dione with different phenyl substituted thiosemicarbazides were synthesized by condensation reaction and the structures of proposed target compounds (KP-2 and KP-5) were confirmed by UV-VIS, FTIR, 1H-NMR and 13C-NMR. In-vitro anti-inflammatory behavior of KP-2 and KP-5 was confirmed by bovine serum albumin (BSA) and ovine serum albumin (OSA) analysis. Acute and chronic anti-inflammatory potential of synthesized compounds were evaluated by using carrageenan and complete Freund's adjuvant (CFA) as inflammation-inducing agents, respectively. Inhibition of pro-inflammatory mediators and prevention of protein denaturation owing to synchronization of more electronegative flouro-groups substituted on phenyl rings along with heterocyclic indoline ring provides anti-inflammatory effects and are corroborated by radiological, histopathological analysis. Additional support was provided through density functional theory (DFT) and molecular docking. KP-5 exhibited excellent lead-likeness based on its physicochemical parameters, making it a viable drug candidate. The synthesized compounds also showed promising ADMET properties, enhancing their potential as therapeutic agents. These findings emphasize the pivotal role of new compounds for drug design and development.


Asunto(s)
Tiosemicarbazonas , Animales , Ovinos , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/uso terapéutico , Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Carragenina , Estructura Molecular , Edema/inducido químicamente , Edema/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa 2/farmacología
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