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1.
Eur J Med Chem ; 242: 114693, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36049274

RESUMO

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the most common. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted the LRRK2 kinase, few have reached clinical trials. We recently reported on the discovery of a novel LRRK2 kinase inhibitor chemotype, 1H-pyrazole biaryl sulfonamides. Although both potent and selective GS-LRRK2 inhibitors, 1H-pyrazole biaryl sulfonamides are incapable of crossing the blood-brain barrier. Retaining the core 1H-pyrazole and focusing our efforts on a phenylsulfonamide bioisosteric replacement, we report the discovery and preliminary development of azaspirocyclic 1H-3,4,5-trisubstituted pyrazoles as potent and selective (>2000-fold) GS-LRRK2 kinase inhibitors capable of entering rodent brain. The compounds disclosed here present an excellent starting point for the development of more brain penetrant compounds.


Assuntos
Doença de Parkinson , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Mutação , Doença de Parkinson/tratamento farmacológico , Inibidores de Proteínas Quinases/metabolismo , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
2.
J Enzyme Inhib Med Chem ; 37(1): 2478-2488, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36073149

RESUMO

The mitochondrial isoforms VA/VB of metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) are involved in metabolic processes, such as de novo lipogenesis and fatty acid biosynthesis. We review the drug design landscape for obtaining CA VA/VB-selective/effective inhibitors, starting from the clinical observations that CA inhibitory drugs, such as the antiepileptics topiramate and zonisamide, or the diuretic acetazolamide induce a significant weight loss. The main approaches for designing such compounds consisted in drug repurposing of already known CA inhibitors (CAIs); screening of synthetic/natural products libraries both in the classical and virtual modes, and de novo drug design using the tail approach. A number of such studies allowed the identification of lead compounds diverse from sulphonamides, such as tropolones, phenols, polyphenols, flavones, glycosides, fludarabine, lenvatinib, rufinamide, etc., for which the binding mode to the enzyme is not always well understood. Classical drug design studies of sulphonamides, sulfamates and sulfamides afforded low nanomolar mitochondrial CA-selective inhibitors, but detailed antiobesity studies were poorly performed with most of them. A breakthrough in the field may be constituted by the design of hybrids incorporating CAIs and other antiobesity chemotypes.


Assuntos
Fármacos Antiobesidade , Anidrases Carbônicas , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Humanos , Obesidade/tratamento farmacológico , Sulfonamidas/farmacologia
3.
Int J Mol Sci ; 23(17)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36077308

RESUMO

Regardless of the significant improvements in treatment of melanoma, the majority of patients develop resistance whose mechanisms are still not completely understood. Hence, we generated and characterized two melanoma-derived cell lines, primary WM793B and metastatic A375M, with acquired resistance to the RAF inhibitor vemurafenib. The morphology of the resistant primary WM793B melanoma cells showed EMT-like features and exhibited a hybrid phenotype with both epithelial and mesenchymal characteristics. Surprisingly, the vemurafenib-resistant melanoma cells showed a decreased migration ability but also displayed a tendency to collective migration. Signaling pathway analysis revealed the reactivation of MAPK and the activation of the PI3K/AKT pathway depending on the vemurafenib-resistant cell line. The acquired resistance to vemurafenib caused resistance to chemotherapy in primary WM793B melanoma cells. Furthermore, the cell-cycle analysis and altered levels of cell-cycle regulators revealed that resistant cells likely transiently enter into cell cycle arrest at the G0/G1 phase and gain slow-cycling cell features. A decreased level of NME1 and NME2 metastasis suppressor proteins were found in WM793B-resistant primary melanoma, which is possibly the result of vemurafenib-acquired resistance and is one of the causes of increased PI3K/AKT signaling. Further studies are needed to reveal the vemurafenib-dependent negative regulators of NME proteins, their role in PI3K/AKT signaling, and their influence on vemurafenib-resistant melanoma cell characteristics.


Assuntos
Melanoma , Proteínas Proto-Oncogênicas B-raf , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico
4.
Molecules ; 27(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36080139

RESUMO

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms.


Assuntos
Anidrase Carbônica I , Anidrases Carbônicas , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Humanos , Estrutura Molecular , Isoformas de Proteínas , Relação Estrutura-Atividade , Sulfanilamida , Sulfonamidas/farmacologia , Tioureia/farmacologia , Ureia
5.
Biomed Pharmacother ; 153: 113473, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076578

RESUMO

Chiral sulfonamides with aromatic fragments are important chemical building blocks found widely in many natural products, catalysts, and molecules of biological importance. In this report, we describe the efficient synthesis of a series of chiral sulfonamides which, in addition to the aromatic part (phenyl, biphenyl, and dansyl units), possess N-heterocyclic systems. The described compounds were obtained by nucleophilic substitution of chiral N-heterocyclic amines and commercially available aromatic sulfonyl chlorides under mild conditions. All derivatives were examined in antiviral assay against AdV5, HSV-1, HPIV-3, HCMV, and EMCV viruses.


Assuntos
Herpesvirus Humano 1 , Sulfonamidas , Aminas , Antivirais/química , Antivirais/farmacologia , Catálise , Sulfonamidas/química , Sulfonamidas/farmacologia
6.
Bioorg Chem ; 128: 106098, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35987189

RESUMO

Insecticides participate with a vital role in our lives especially in preventing the spread of human diseases via controlling the dangerous pests. It is a challenge to identify alternatives to the ordinary insecticides with new mode of action to be used for mosquitoes' control in an environmentally sustainable manner. Using a facile two-step procedure, three novel series of sulfonamide-incorporating quaternary ammonium iodides (3a-i, 4a-i and 5a-i) were synthesized and their chemical structures were successfully characterized. The uncharged sulfonamide intermediates (2a-i) were constructed through simple amidation of the corresponding (hetero)aryl sulfonyl chlorides then the cationic target molecules were formed by quaternizing the tertiary nitrogen with methyl, ethyl, and allyl iodides. The larvicidal activities and biological effects of most synthesized compounds against Culex pipiens L. were extensively investigated and they exhibited good and comparable activities to temephos. Among these hybrids, 4a showed the most potent activity with LC50 = 26.71 ppm. Additionally, the developmental durations of larval and pupal stages were significantly prolonged after treatment with all concentrations of 4h. At high concentration (160 ppm) of 4a and 4b, no adults emerged due to the complete death of pupae, and consequently zero growth index. Moreover, the results of the molecular docking demonstrated that the activities of compounds correlate partially to their binding with acetylcholinesterase (AChE) and it is not the sole parameter for determining the activity.


Assuntos
Compostos de Amônio , Culex , Inseticidas , Acetilcolinesterase , Compostos de Amônio/farmacologia , Animais , Inibidores da Colinesterase/farmacologia , Humanos , Inseticidas/química , Inseticidas/farmacologia , Iodetos , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia
7.
Sci Rep ; 12(1): 14280, 2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-35995819

RESUMO

Antagonism of the angiotensin II type 1 receptor (AT1) improves neurological function and reduces brain damage after experimental traumatic brain injury (TBI), which may be partly a result of enhanced indirect angiotensin II type 2 receptor (AT2) stimulation. AT2 stimulation was demonstrated to be neuroprotective via anti-inflammatory, vasodilatory, and neuroregenerative mechanisms in experimental cerebral pathology models. We recently demonstrated an upregulation of AT2 after TBI suggesting a protective mechanism. The present study investigated the effect of post-traumatic (5 days after TBI) AT2 activation via high and low doses of a selective AT2 agonist, compound 21 (C21), compared to vehicle-treated controls. No differences in the extent of the TBI-induced lesions were found between both doses of C21 and the controls. We then tested AT2-knockdown animals for secondary brain damage after experimental TBI. Lesion volume and neurological outcomes in AT2-deficient mice were similar to those in wild-type control mice at both 24 h and 5 days post-trauma. Thus, in contrast to AT1 antagonism, AT2 modulation does not influence the initial pathophysiological mechanisms of TBI in the first 5 days after the insult, indicating that AT2 plays only a minor role in the early phase following trauma-induced brain damage.


Assuntos
Lesões Encefálicas Traumáticas , Receptor Tipo 2 de Angiotensina , Animais , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/patologia , Imidazóis/farmacologia , Masculino , Camundongos , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina/metabolismo , Sulfonamidas/farmacologia , Tiofenos/farmacologia
8.
Molecules ; 27(16)2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-36014478

RESUMO

In the present study, new 2-phenyl-5,6,7,8-tetrahydroimidazo [1,2-b]pyridazines bearing sulfonamides were synthesized, characterized and evaluated for their anticancer activities. The structures of these derivatives were elucidated by 1H NMR, 13C NMR, infrared and high-resolution mass spectrometry for further validation of the target compound structures. The anticancer activities of the new molecules were evaluated against five human cancer cell lines, including A-549, Hs-683, MCF-7, SK-MEL-28 and B16-F10 cell lines using 5-fluorouracil and etoposide as the reference drugs. Among the tested compounds, 4e and 4f exhibited excellent activities in the same range of the positive controls, 5-fluorouracil and etoposide, against MCF-7 and SK-MEL-28 cancer cell lines, with IC50 values ranging from 1 to 10 µM. The molecular docking studies of 4e and 4f showed a strong binding with some kinases, which are linked to MCF-7 and SK-MEL-28 cancer cell lines.


Assuntos
Antineoplásicos , Neoplasias , Piridazinas , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Etoposídeo/farmacologia , Fluoruracila/farmacologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias/tratamento farmacológico , Piridazinas/química , Relação Estrutura-Atividade , Sulfanilamida/farmacologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
9.
Huan Jing Ke Xue ; 43(8): 4166-4178, 2022 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-35971714

RESUMO

Antibiotics and antibiotic resistance genes (ARGs) in livestock and poultry manure pose potential ecological risks. In order to understand the distribution characteristic of antibiotics and ARGs in manure and surrounding soils of poultry farms in Ningxia, the poultry manure and relative soil samples were collected from 12 layers of different poultry breeding farms. The compositions of antibiotics and ARGs in the samples were analyzed using UPLC-MS/MS and HT-qPCR. The results showed that:① tetracycline, aminoglycoside, and sulfonamide were the dominant antibiotics in poultry manure. The types and contents of antibiotics in poultry manure were different in different breeding periods. There were more types of antibiotics in the brooding period, the average content was high, and the initial stage showed the opposite trend. ② A small amount of antibiotics was detected in the surrounding soil only 20 m away from the poultry farm, and the poultry farm had little effect on the distribution of antibiotics in the surrounding soil. The content of quinolone in the soils with poultry manure application was significantly higher than that in the control and surrounding soil. ③ We detected 132-168 ARGs in poultry manure, and the number of aminoglycosides and tetracycline was higher. The relative abundance of ARGs in the rearing period was highest, and the initial stage showed the opposite trend. The total relative abundance of ARGs in the brooding period was highest, but the terminal period showed the opposite. There were 110 ARGs in poultry manure during all breeding periods. ④ There were 23-105 ARGs in the soils, and the number of aminoglycoside was highest, followed by multidrug ARGs. The poultry farm had a great effect on the number and relative abundance of ARGs in the surrounding soil. For example, the number and relative abundance of ARGs in the surrounding soil of poultry farms gradually decreased with the increase in the distance from the poultry farms. The number and relative abundance of ARGs in the soil with applied poultry manure were significantly increased; however, these values were lower than those in the soil 20 m away from the poultry farm. ⑤ ß-lactamases, aminoglycosides, and macrolide lincosamide-streptogramin B (MLSB) ARGs were all at risk of horizontal movement in manure, and chloramphenicol ARGs were at risk of horizontal movement in soil. Correlation analysis showed that the relative abundance of aminoglycoside, tetracycline, sulfonamide, ß-lactamase, and MLSB were not significantly correlated with their contents. ⑥ Different types of ARGs had related co-occurrence phenomena, such as the positive correlation between the relative abundance of ARGs in poultry manure, and aminoglycoside and ß-lactamases, MGEs, multidrugs and vancomycins. The relative abundances of ARGs in soil, aminoglycoside and tetracyclines, vancomycins, sulfonamides, and MLSBs; tetracyclines and MLSBs; etc., all showed a significant positive correlation. In short, the co-occurrence among the relative abundance of ARGs in soil was significantly stronger than that in poultry manure. These results could provide the theoretical basis for the site selection of poultry farms, the selection of antibiotic types and dosages for large-scale breeding of laying hens, and the application of poultry manure.


Assuntos
Esterco , Solo , Aminoglicosídeos/farmacologia , Animais , Antibacterianos/farmacologia , Galinhas/genética , Cromatografia Líquida , Resistência Microbiana a Medicamentos/genética , Fazendas , Feminino , Genes Bacterianos , Macrolídeos/farmacologia , Esterco/análise , Aves Domésticas/genética , Microbiologia do Solo , Sulfonamidas/farmacologia , Espectrometria de Massas em Tandem , Tetraciclina/farmacologia , Tetraciclinas/farmacologia , beta-Lactamases/genética
10.
Bioorg Chem ; 128: 106086, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35973306

RESUMO

In this article, we report the synthesis of Celecoxib derivatives containing the pyrazole-linked sulfonamide moiety. The enzyme inhibition effects of these derivatives on aldose reductase (AR) were also investigated. The IC50 values of the pyrazole sulfonamide derivatives were determined to be in the range of 40.76-8.25 µM. Among the synthesized derivatives, the compound 16 showed the strongest inhibition effect against the AR enzyme, with an IC50 value of 8.25 µM. Molecular docking studies were carried out to determine the interactions of the synthesized compounds with the AR enzyme, and ADMET studies were performed to assess the pharmacokinetic and drug-likeness properties.


Assuntos
Aldeído Redutase , Pirazóis , Celecoxib/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/farmacologia , Relação Estrutura-Atividade , Sulfanilamida , Sulfonamidas/farmacologia
11.
Bioorg Med Chem Lett ; 73: 128892, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35850422

RESUMO

NaV1.7 is an actively pursued, genetically validated, target for pain. Recently reported quinolinone sulfonamide inhibitors displayed promising selectivity profiles as well as efficacy in preclinical pain models; however, concerns about off-target liabilities associated with this series resulted in an effort to reduce the lipophilicity of these compounds. Successful prosecution of this strategy was challenging due to the opposing requirement for lipophilic inhibitors for NaV1.7 potency and in vivo clearance (CL). Deconstruction of the heterocyclic core of the quinolinone series and utilization of an intramolecular hydrogen bond to mimic the requisite pharmacophore enabled the introduction of polarity without adversely impacting CL. Ultimately, this strategy led to the identification of compound 29, which demonstrated favorable ADME and was efficacious in pre-clinical models of pain.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7 , Quinolonas , Humanos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/tratamento farmacológico , Relação Estrutura-Atividade , Sulfanilamida , Sulfonamidas/química , Sulfonamidas/farmacologia , Ureia/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/química
12.
Molecules ; 27(13)2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35807212

RESUMO

Sulfonamides are a classic group of chemotherapeutic drugs with a broad spectrum of pharmacological action, including anticancer activity. In this work, reversed-phase high-performance liquid chromatography and biomimetic chromatography were applied to characterize the lipophilicity of sulfonamide derivatives with proven anticancer activities against human colon cancer. Chromatographically determined lipophilicity parameters were compared with obtained logP, employing various computational approaches. Similarities and dissimilarities between experimental and computational logP were studied using principal component analysis, cluster analysis, and the sum of ranking differences. Furthermore, quantitative structure-retention relationship modeling was applied to understand the influences of sulfonamide's molecular properties on lipophilicity and affinity to phospholipids.


Assuntos
Quimiometria , Cromatografia de Fase Reversa , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa/métodos , Análise por Conglomerados , Humanos , Análise de Componente Principal , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/farmacologia
13.
Biomolecules ; 12(7)2022 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-35883549

RESUMO

Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively dimerizes and conveys drug resistance. Here, we have analysed AS in SK-MEL-239 melanoma cells and a BRAF inhibitor (vemurafenib)-resistant derivative that expresses an AS, shortened BRAF V600E transcript. Transcriptome analysis showed differential expression of spliceosome components between the two cell lines. As there is no consensus approach to analysing AS events, we used and compared four common AS softwares based on different principles, DEXSeq, rMATS, ASpli, and LeafCutter. Two of them correctly identified the BRAF V600E AS in the vemurafenib-resistant cells. Only 12 AS events were identified by all four softwares. Testing the AS predictions experimentally showed that these overlapping predictions are highly accurate. Interestingly, they identified AS caused alterations in the expression of melanin synthesis and cell migration genes in the vemurafenib-resistant cells. This analysis shows that combining different AS analysis approaches produces reliable results and meaningful, biologically testable hypotheses.


Assuntos
Antineoplásicos , Melanoma , Processamento Alternativo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Indóis/farmacologia , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , RNA Mensageiro/metabolismo , Sulfonamidas/farmacologia , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico
14.
Int J Mol Sci ; 23(14)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35887037

RESUMO

(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (Ki = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (Ki > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (Ki = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions.


Assuntos
Neoplasias , Sulfonamidas , Antígenos de Neoplasias/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Humanos , Estrutura Molecular , Quinina/análogos & derivados , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
15.
Cell Death Dis ; 13(6): 571, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35760785

RESUMO

The ß2-adrenergic receptor (ß2AR) is a G protein-coupled receptor (GPCR) that mediates the majority of cellular responses to external stimuli. Aberrant expression of ß2AR results in various pathophysiological disorders, including tumorigenesis, but little is known about its role in liver regeneration. This study aims to investigate the impact and the underlying mechanism of ß2AR in liver regeneration. Here, we found that ß2AR was upregulated during liver regeneration induced by 70% PH. Deletion of ß2AR in mice resulted in 62% mortality 2 days post-PH, decreased proliferative marker expression and impaired liver function throughout regeneration. Moreover, AAV8-mediated overexpression of ß2AR in hepatocytes accelerated the regeneration process and increased target gene expression. Mechanistically, ß2AR recruited G-protein-coupled receptor kinase 2 (GRK2) to the membrane and then formed a complex with c-met to transactivate c-met signaling, which triggered downstream extracellular regulated protein kinase (ERK) signaling activation and nuclear translocation. Inhibition of c-met with SU11274 or ERK with U0126 decreased ß2AR overexpression-induced hepatocyte proliferation. Our findings revealed that ß2AR might act as a critical mediator regulating liver regeneration by crosstalk with c-met and activation of ERK signaling.


Assuntos
Regeneração Hepática , Transdução de Sinais , Animais , Camundongos , Fosforilação , Transporte Proteico , Sulfonamidas/farmacologia
16.
Molecules ; 27(12)2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35744887

RESUMO

In this paper, we present for the first time the evaluation of cytotoxicity and genotoxicity of de novo synthesized pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides MM129, MM130, and MM131 in human tumor cell lines: HeLa, HCT 116, PC-3, and BxPC-3. Cytotoxic and genotoxic properties of the tested compounds were estimated using the MTT assay, comet assay (alkaline and neutral version), and γ-H2AX immuno-staining. Examined sulfonamides exhibited strong anticancer properties towards tested cells in a very low concentration range (IC50 = 0.17-1.15 µM) after 72 h exposure time. The results of the alkaline and neutral version of the comet assay following 24 h incubation of the cells with tested compounds demonstrated the capability of heterocycles to induce significant DNA damage in exposed cells. HCT 116 cells were the most sensitive to the genotoxic activity of novel tricyclic pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides in the neutral version of the comet assay. Immunocytochemical detection of γ-H2AX showed an increase in DNA DSBs level in the HCT 116 cell line, after 24 h incubation with all tested compounds, confirming the results obtained in the neutral comet assay. Among all investigated compounds, MM131 showed the strongest cytotoxic and genotoxic activity toward all tested cell types. In conclusion, our results suggest that MM129, MM130, and MM131 exhibit high cytotoxic and genotoxic potential in vitro, especially towards the colorectal cancer cell line HCT 116. However, further investigations and analyses are required for their future implementation in the field of medicine.


Assuntos
Antineoplásicos , Triazinas , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaio Cometa , Dano ao DNA , Humanos , Sulfanilamida , Sulfonamidas/farmacologia , Triazinas/química , Triazinas/farmacologia
17.
J Enzyme Inhib Med Chem ; 37(1): 1737-1751, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35707920

RESUMO

A new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to enhance antibacterial activity for treatment of septicaemia. Compounds 5 b, 5j, 5n and 5o demonstrated potent in vitro COX-2 inhibitory activity comparable to celecoxib. 5j and 5o exhibited ED50 lower than celecoxib in carrageenan-induced paw edoema test with % PGE2 inhibition higher than celecoxib. Furthermore, 5 b, 5j and 5n showed gastric safety profile like celecoxib. Moreover, in vivo antibacterial screening revealed that, 5j showed activity against S.aureus and E.coli higher than sulfasalazine. While, 5o revealed activity against E.coli higher than sulfasalazine and against S.aureus comparable to sulfasalazine. Compound 5j achieved the target goal as potent inhibitor of COX-2/PGE2 axis and in vivo broad-spectrum antibacterial activity against induced septicaemia in mice.


Assuntos
Inibidores de Ciclo-Oxigenase 2 , Di-Hidropteroato Sintase , Inibidores Enzimáticos , Sepse , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/efeitos adversos , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2/farmacologia , Di-Hidropteroato Sintase/antagonistas & inibidores , Dinoprostona , Edema/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Camundongos , Sepse/tratamento farmacológico , Sulfassalazina/farmacologia , Sulfonamidas/farmacologia
18.
Br J Cancer ; 127(6): 1142-1152, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35725813

RESUMO

BACKGROUND: Disseminated BRAFV600E melanoma responds to BRAF inhibitors (BRAFi) but easily develops resistance with poor prognosis. Secretome plays a pivotal role during tumour progression causing profound effects on therapeutic efficacy. Secreted M-CSF is involved in both cytotoxicity suppression and tumour progression in melanoma. We aimed to analyse the M-CSF contribution in resistant metastatic melanoma to BRAF-targeted therapies. METHODS: Conditioned media from melanoma cells were analysed by citoarray. Viability and migration/invasion assays were performed with paired melanoma cells and tumour growth in xenografted SCID mice. We evaluated the impact of M-CSF plasma levels with clinical prognosis from 35 metastatic BRAFV600E-mutant melanoma patients. RESULTS: BRAFi-resistant melanoma cells secretome is rich in pro-tumour cytokines. M-CSF secretion is essential to induce a Vemurafenib-resistant phenotype in melanoma cells. Further, we demonstrated that M-CSF mAb in combination with Vemurafenib and autophagy blockers synergistically induce apoptosis, impair migration and reduce tumour growth in BRAFi-resistant melanoma cells. Interestingly, lower M-CSF plasma levels are associated with better prognosis in metastatic melanoma patients. CONCLUSIONS: Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAFV600E metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.


Assuntos
Melanoma , Proteínas Proto-Oncogênicas B-raf , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Indóis/farmacologia , Indóis/uso terapêutico , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/farmacologia , Fator Estimulador de Colônias de Macrófagos/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos SCID , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/farmacologia , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico
19.
Future Med Chem ; 14(14): 1049-1070, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35707942

RESUMO

Aim: This study reports the designing of BChE inhibitors through machine learning (ML), followed by in silico and in vitro evaluations. Methodology: ML technique was used to predict the virtual hit, and its derivatives were synthesized and characterized. The compounds were evaluated by using various in vitro tests and in silico methods. Results: The gradient boosting classifier predicted N-phenyl-4-(phenylsulfonamido) benzamide as an active BChE inhibitor. The derivatives of the inhibitor, i.e., compounds 34, 37 and 54 were potent BChE inhibitors and displayed blood-brain barrier permeability with no significant AChE inhibition. Conclusion: The ML prediction was effective, and the synthesized compounds showed the BChE inhibitory activity, which was also supported by the in silico studies.


Assuntos
Butirilcolinesterase , Inibidores da Colinesterase , Inibidores da Colinesterase/farmacologia , Aprendizado de Máquina , Sulfonamidas/farmacologia
20.
Bioresour Technol ; 358: 127431, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35671911

RESUMO

Both co-cultivation and co-substrate addition strategies have exhibited massive potential in microalgae-based antibiotic bioremediation. In this study, glucose and sodium acetate were employed as co-substrate in the cultivation of microalgae-bacteria consortium for enhanced sulfadiazine (SDZ) and sulfamethoxazole (SMX) removal. Glucose demonstrated a two-fold increase in biomass production with a maximum specific growth rate of 0.63 ± 0.01 d-1 compared with sodium acetate. The supplementation of co-substrate enhanced the degradation of SDZ significantly up to 703 ± 18% for sodium acetate and 290 ± 22% for glucose, but had almost no effect on SMX. The activities of antioxidant enzymes, including peroxidase, superoxide dismutase and catalase decreased with co-substrate supplementation. Chlorophyll a was associated with protection against sulfonamides and chlorophyll b might contribute to SDZ degradation. The addition of co-substrates influenced bacterial community structure greatly. Glucose enhanced the relative abundance of Proteobacteria, while sodium acetate improved the relative abundance of Bacteroidetes significantly.


Assuntos
Microalgas , Bactérias , Clorofila A/metabolismo , Suplementos Nutricionais , Glucose/metabolismo , Microalgas/metabolismo , Acetato de Sódio/metabolismo , Acetato de Sódio/farmacologia , Sulfadiazina/metabolismo , Sulfametoxazol/metabolismo , Sulfanilamida/metabolismo , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia
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