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1.
Molecules ; 26(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34361550

RESUMO

Efficient use of herbicides for plant protection requires the application of auxiliary substances such as surfactants, stabilizers, wetting or anti-foaming agents, and absorption enhancers, which can be more problematic for environment than the herbicides themselves. We hypothesized that the combination of sulfonylurea (iodosulfuron-methyl) anion with inexpensive, commercially available quaternary tetraalkylammonium cations could lead to biologically active ionic liquids (ILs) that could become a convenient and environment-friendly alternative to adjuvants. A simple one-step synthesis allowed for synthesizing iodosulfuron-methyl based ILs with high yields ranging from 88 to 96% as confirmed by UV, FTIR, and NMR. The obtained ILs were found to possess several favorable properties compared to the currently used sodium salt iodosulfuron-methyl, such as adjustable hydrophobicity (octanol-water partition coefficient) and enhanced stability in aqueous solutions, which was supported by molecular calculations showing cation-anion interaction energies. In addition, soil mobility and volatility of ILs were more beneficial compared to the parental herbicide. Herbicidal activity tests toward oil-seed rape and cornflower revealed that ILs comprising at least one alkyl chain in the decyl to octadecyl range had similar or better efficacy compared to the commercial preparation without addition of any adjuvant. Furthermore, results of antimicrobial activity indicated that they were practically harmless or slightly toxic toward model soil microorganisms such as Pseudomonas putida and Bacillus cereus.


Assuntos
Anti-Infecciosos/química , Herbicidas/química , Líquidos Iônicos/química , Sulfonamidas/química , Compostos de Sulfonilureia/química , Tensoativos/química , Anti-Infecciosos/farmacologia , Bacillus cereus/crescimento & desenvolvimento , Herbicidas/farmacologia , Pseudomonas putida/crescimento & desenvolvimento , Compostos de Sulfonilureia/farmacologia
2.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445408

RESUMO

The mechanism of sulfisoxazole (SFF) selective removal by photocatalysis in the presence of titanium (IV) oxide (TiO2) and iron (III) chloride (FeCl3) was explained and the kinetics and degradation pathways of SFF and other antibiotics were compared. The effects of selected inorganic ions, oxygen conditions, pH, sorption processes and formation of coordination compounds on the photocatalytic process in the presence of TiO2 were also determined. The Fe3+ compounds added to the irradiated sulfonamide (SN) solution underwent surface sorption on TiO2 particles and act as acceptors of excited electrons. Most likely, the SFF degradation is also intensified by organic radicals or cation organic radicals. These radicals can be initially generated by reaction with electron holes, hydroxyl radicals and as a result of electron transfer mediated by iron ions and then participate in propagation processes. The high sensitivity of SFF to decomposition caused by organic radicals is associated with the steric effect and the high bond polarity of the amide substituent.


Assuntos
Antibacterianos/química , Sulfonamidas/química , Titânio/química , Catálise , Concentração de Íons de Hidrogênio , Cinética , Compostos Orgânicos , Fotólise , Sulfisoxazol/química , Purificação da Água
3.
J Enzyme Inhib Med Chem ; 36(1): 1874-1883, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340614

RESUMO

A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Biologia Computacional/métodos , Isoenzimas/antagonistas & inibidores , Quinazolinas/química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , Sulfonamidas/química
4.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445506

RESUMO

Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Triterpenos Pentacíclicos/química , Sulfonamidas/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Antígenos de Neoplasias/química , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Simulação de Acoplamento Molecular , Tolerância a Radiação , Sulfonamidas/síntese química , Sulfonamidas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
5.
Molecules ; 26(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34443307

RESUMO

A novel series of tri-aryl imidazole derivatives 5a-n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3-1.3 µM, and selectivity ratio for hCA IX over hCA XII = 5-12) relative to acetazolamide (Ki = 0.03 µM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than other tested compounds (with GI50 = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI50 = 1.1 M). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK. Molecular modelling simulation showed good agreement with the acquired biological evaluation.


Assuntos
Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Biologia Computacional , Desenho de Fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Sulfonamidas/síntese química , Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Humanos , Imidazóis/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
6.
Biomolecules ; 11(7)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356673

RESUMO

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.


Assuntos
Antineoplásicos/uso terapêutico , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Celecoxib/efeitos adversos , Celecoxib/análogos & derivados , Celecoxib/farmacologia , Ciclo Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Pirazóis/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Sulfonamidas/farmacologia
7.
Bioorg Chem ; 114: 105153, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34328851

RESUMO

A series of novel substituted phenyl 1, 3-thiazolidin-4-one sulfonyl derivatives 5 (a-t) were synthesized and screened for their in-vitro anti-microbial and anti-viral activity. The result of the anti-microbial assay demonstrated compounds 5d, 5f, 5g, 5h, 5i, 5j showed prominent inhibitory activity against all the tested Gram-positive and Gram-negative bacterial strains, while compounds 5g, 5j, 5o, 5p, 5q showed significant activity against the entire set of fungal strains as compared to standard drug Ampicillin and Clotrimazole, respectively. The antimicrobial study revealed that compounds having electron-withdrawing groups showed significant antimicrobial potency. The most active antibacterial compound 5j showed potent inhibition of S. aureus DNA Gyrase enzyme as a possible mechanism of action for antimicrobial activity. Moreover, the antiviral testing of selected compounds showed considerable activity against Herpes simplex virus-1(KOS), Herpes simplex virus-2 (G), Herpes simplex virus-1(TK- KOS ACVr), Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Sindbis virus, Coxsackie virus B4, Yellow Fever virus and Influenza A, B virus. Compounds 5h exhibited low anti-viral activity against HIV-1(strain IIIB) and HIV-2 (strain ROD). The study clearly outlined that synthesized compounds endowed with good antimicrobial property together with considerable antiviral activity.


Assuntos
Fenóis/síntese química , Sulfonamidas/síntese química , Tolueno/análogos & derivados , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Linhagem Celular , Chlorocebus aethiops , Humanos , Fenóis/química , Fenóis/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tolueno/síntese química , Tolueno/química , Tolueno/farmacologia , Células Vero , Vírus/classificação , Vírus/efeitos dos fármacos
8.
J Chem Theory Comput ; 17(8): 5409-5418, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34259506

RESUMO

A major challenge in understanding ligand binding to biomacromolecules lies in dissecting the underlying thermodynamic driving forces at the atomic level. Quantifying the contributions of water molecules is often especially demanding, although they can play important roles in biomolecular recognition and binding processes. One example is human carbonic anhydrase II, whose active site harbors a conserved network of structural water molecules that are essential for enzymatic catalysis. Inhibitor binding disrupts this water network and changes the hydrogen-bonding patterns in the active site. Here, we use atomistic molecular dynamics simulations to compute the absolute entropy of the individual water molecules confined in the active site of hCAII using a spectrally resolved estimation (SRE) approach. The entropy decrease of water molecules that remain in the active site upon binding of a dorzolamide inhibitor is caused by changes in hydrogen bonding and stiffening of the hydrogen-bonding network. Overall, this entropy decrease is overcompensated by the gain due to the release of three water molecules from the active site upon inhibitor binding. The spectral density calculations enable the assignment of the changes to certain vibrational modes. In addition, the range of applicability of the SRE approximation is systematically explored by exploiting the gradually changing degree of immobilization of water molecules as a function of the distance to a phospholipid bilayer surface, which defines an "entropy ruler". These results demonstrate the applicability of SRE to biomolecular solvation, and we expect it to become a useful method for entropy calculations in biomolecular systems.


Assuntos
Anidrase Carbônica II/química , Água/química , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Domínio Catalítico , Entropia , Humanos , Ligação de Hidrogênio , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Ligação Proteica , Sulfonamidas/química , Sulfonamidas/metabolismo , Tiofenos/química , Tiofenos/metabolismo
9.
J Enzyme Inhib Med Chem ; 36(1): 1521-1539, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34266349

RESUMO

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4-24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59-14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 µM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 µM, respectively) and HER2 (IC50 = 0.13 and 0.07 µM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.


Assuntos
Antineoplásicos/farmacologia , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/química , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
10.
J Enzyme Inhib Med Chem ; 36(1): 1563-1572, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34281464

RESUMO

A series of tertiary sulphonamide derivatives were synthesised and evaluated for their antiproliferative activity against liver cancer cell lines (SNU-475, HepG-2, and Bel-7402). Among these tertiary sulphonamides, compound 17a displayed the best anti-liver cancer activity against Bel-7402 cells with an IC50 value of 0.32 µM. Compound 17a could effectively inhibit tubulin polymerisation with an IC50 value of 1.27 µM. Meanwhile, it selectively suppressed LSD1 with an IC50 value of 63 nM. It also concentration-dependently inhibited migration against Bel-7402 cells. Importantly, tertiary sulphonamide 17a exhibited the potent antitumor activity in vivo. All these findings revealed that compound 17a might be a tertiary sulphonamide-based dual inhibitor of tubulin polymerisation and LSD1 to treat liver cancer.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Polimerização/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
11.
Nat Commun ; 12(1): 4065, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210971

RESUMO

Strategies that enable intermolecular site-selective C-H bond functionalisation of organic molecules provide one of the cornerstones of modern chemical synthesis. In chloroalkane synthesis, such methods for intermolecular site-selective aliphatic C-H bond chlorination have, however, remained conspicuously rare. Here, we present a copper(I)-catalysed synthetic method for the efficient site-selective C(sp3)-H bond chlorination of ketones, (E)-enones and alkylbenzenes by dichloramine-T at room temperature. A key feature of the broad substrate scope is tolerance to unsaturation, which would normally pose an immense challenge in chemoselective aliphatic C-H bond functionalisation. By unlocking dichloramine-T's potential as a chlorine radical atom source, the product site-selectivities achieved are among the most selective in alkane functionalisation and should find widespread utility in chemical synthesis. This is exemplified by the late-stage site-selective modification of a number of natural products and bioactive compounds, and gram-scale preparation and formal synthesis of two drug molecules.


Assuntos
Domínio Catalítico , Cobre/química , Cetonas/química , Sulfonamidas/química , Produtos Biológicos/química , Carbono/química , Catálise , Halogenação , Hidrogênio/química , Temperatura
12.
Eur J Med Chem ; 222: 113585, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34118722

RESUMO

Cancer immunotherapy has become a research hotspot in recent years. A variety of targets were developed for small molecule immuno-oncology agents, including retinoic acid-related orphan receptor gamma t (RORγt), chemokine receptor, stimulator of interferon genes (Sting), indoleamine 2,3-dioxygenase (IDO), toll-like receptors (TLR), etc. Among them, the retinoic acid receptor-related orphan receptor γt (RORγt) has gradually attracted more attention in these years. In particular, LYC-55716 (cintirorgon), a small molecule RORγt agonist developed by Lycera, has entered the phase II clinical study. In this work, starting from compound 7, compound 28 was obtained after 4 rounds of compound design, synthesis and SAR studies, which had an EC50 of 0.021 ± 0.002 µM in dual Fluorescence Resonance Energy Transfer (dual-FRET) assay and an EC50 of 0.021 ± 0.002 µM in mouse Th17 cell differentiation assay. It indicated that compound 28 had excellent RORγt agonistic activity and was expected to be developed as a new type of small molecule drug for cancer immunotherapy. The molecular dynamic simulation revealed that the agonist 28 formed a strong HYF triplet intramolecular interaction to stabilize H12, which helped RORγt to form the protein-binding site and therefore made the receptor ready to recruit coactivator. When the inverse agonist s27 bound with RORγt, the steric hindrance between s27 and H479 caused the destruction of the HYF triplet, leading to the collapse of H12, thus the transcription function of RORγt was interrupted due to the failure of recruiting a coactivator molecule. The triplet HYF in RORγt and the rigidity of 28 and s27 were identified to be the structural determinants for the functional switch of RORγt.


Assuntos
Descoberta de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sulfonamidas/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química
13.
Eur J Med Chem ; 222: 113599, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34119834

RESUMO

Blocking the Kelch-like epichlorohydrin-related protein 1 (Keap1)-nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway represents as a promising strategy to reduce oxidative stress and related-inflammation, including acute lung injury (ALI). NXPZ-2, a naphthalensulfonamide derivative, was previously reported to effectively inhibit the Keap1-Nrf2 protein-protein interaction (PPI) by our group. In the present work, a series of novel isothiocyanate-containing naphthalensulfonamides with the thioether, sulfoxide and sulfone moieties were designed by a structure-based molecular hybridization strategy using NXPZ-2 and the Nrf2 activator sulforaphane. They possessed good Keap1-Nrf2 PPI inhibitory activity and low cytotoxicity. The molecular docking study was performed to further explain the different activity of the thioether-, sulfoxide- and sulfone-containing naphthalensulfonamides. Among these new derivatives, 2-((N-(4-((N-(2-amino-2-oxoethyl)-4-((3-isothiocyanatopropyl)sulfinyl)phenyl)sulfonamido) naphthalen-1-yl)-4-methoxyphenyl)sulfonamido)acetamide (SCN-16) showed a good KD2 value of 0.455 µM to disrupt the PPI. In an LPS-induced peritoneal macrophage cell model, this compound could cause a significant increase in the nuclear Nrf2 protein, decrease in the cytosolic Nrf2 protein, and further elevate the downstream protective enzymes HO-1 and NQO-1, which were better than the lead compound NXPZ-2 and sulforaphane. What's more, the production of ROS and NO and the expression of pro-inflammatory cytokine TNF-α were also suppressed. In the LPS-induced ALI model, SCN-16 could significantly reduce LPS-induced inflammations and alleviate lung injuries by triggering Nrf2 nuclear translocation. Collectively, our results suggested that SCN-16 could be a novel lead compound targeting Keap1-Nrf2 protective pathway for clinical treatment of ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Naftalenos/farmacologia , Substâncias Protetoras/farmacologia , Sulfonamidas/farmacologia , Lesão Pulmonar Aguda/metabolismo , Animais , Relação Dose-Resposta a Droga , Desenho de Fármacos , Feminino , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Naftalenos/síntese química , Naftalenos/química , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
14.
J Enzyme Inhib Med Chem ; 36(1): 1402-1410, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34157927

RESUMO

A new series of sulphonamide derivatives bearing naphthalene moiety were synthesised and evaluated for their antiproliferative and tubulin polymerisation inhibitory activities. These new compounds were evaluated for their in vitro antiproliferative activity against MCF-7 and A549 by using CCK-8 method. Among all the tested compounds, compound 5c with naphthalen-1-yl moiety exhibited the most potent antiproliferative activity against MCF-7 and A549 cell line, with IC50 values of 0.51 ± 0.03 µM and 0.33 ± 0.01 µM, respectively. The results of tubulin polymerisation assay shown that 5c exhibited a significant ability to inhibit tubulin polymerisation with IC50 value of 2.8 µM. Consistent with its antitubulin activity, 5c can significantly arrest the cell cycle at G2/M phase and induce apoptosis in MCF-7 cancer cells. Molecular docking study indicated that compound 5c inhibited tubulin polymerisation through interacting at the colchicine-binding site of tubulin. Furthermore, 5c exhibited low cytotoxic activity on human normal cell line.


Assuntos
Antineoplásicos/farmacologia , Naftalenos/química , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Moduladores de Tubulina/química
15.
Eur J Med Chem ; 221: 113566, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34077833

RESUMO

Seventeen new amide/sulfonamide containing nimesulide derivatives were synthesized and characterized by several spectroscopic techniques and primarily investigated for their inhibitory potential on COX enzymes and other pro-inflammatory factors. Experimental analyses showed that among seventeen compounds, N8 and N10 have remarkable potency and selectivity for the COX-2 enzyme over COX-1 at very low doses as compared to nimesulide. Moreover, both N8 and N10 selectively reduced the Lipopolysaccharide (LPS)-stimulated COX-2 mRNA expression level while the COX-1 level remained stable. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed by the N8 and N10 treatment groups. In silico ADME/Tox, molecular docking and molecular dynamics (MD) simulations were also conducted. Additionally, all compounds were also screened in a panel of cancer cell lines for their antiproliferative properties by MTT and SRB assays. Compound N17 exhibited a considerable antiproliferative effect on the colon (IC50: 9.24 µM) and breast (IC50: 11.35 µM) cancer cell lines. N17 exposure for 48 h decreased expression of anti-apoptotic protein BCL-2 and increased the expression of apoptogenic BAX. Besides, the BAX/BCL-2 ratio was increased with visible ultrastructural changes and apoptotic bodies under scanning electron microscopy. In order to investigate the structural and dynamical properties of selected hits on the target structures, multiscale molecular modeling studies are also conducted. Our combined in silico and in vitro results suggest that N8 and N10 could be further developed as potential nonsteroidal anti-inflammatory drugs (NSAIDs), while cytotoxic N17 might be studied as a potential lead compound that could be developed as an anticancer agent.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Sulfonamidas/farmacologia , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
16.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073245

RESUMO

Metformin, apart from its glucose-lowering properties, has also been found to demonstrate anti-cancer properties. Anti-cancer efficacy of metformin depends on its uptake in cancer cells, which is mediated by plasma membrane monoamine transporters (PMAT) and organic cation transporters (OCTs). This study presents an analysis of transporter mediated cellular uptake of ten sulfonamide-based derivatives of metformin in two breast cancer cell lines (MCF-7 and MDA-MB-231). Effects of these compounds on cancer cell growth inhibition were also determined. All examined sulfonamide-based analogues of metformin were characterized by greater cellular uptake in both MCF-7 and MDA-MB-231 cells, and stronger cytotoxic properties than those of metformin. Effective intracellular transport of the examined compounds in MCF-7 cells was accompanied by high cytotoxic activity. For instance, compound 2 with meta-methyl group in the benzene ring inhibited MCF-7 growth at micromolar range (IC50 = 87.7 ± 1.18 µmol/L). Further studies showed that cytotoxicity of sulfonamide-based derivatives of metformin partially results from their ability to induce apoptosis in MCF-7 and MDA-MB-231 cells and arrest cell cycle in the G0/G1 phase. In addition, these compounds were found to inhibit cellular migration in wound healing assay. Importantly, the tested biguanides are more effective in MCF-7 cells at relatively lower concentrations than in MDA-MB-231 cells, which proves that the effectiveness of transporter-mediated accumulation in MCF-7 cells is related to biological effects, including MCF-7 cell growth inhibition, apoptosis induction and cell cycle arrest. In summary, this study supports the hypothesis that effective transporter-mediated cellular uptake of a chemical molecule determines its cytotoxic properties. These results warrant a further investigation of biguanides as putative anti-cancer agents.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Biguanidas , Neoplasias da Mama , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sulfonamidas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Biguanidas/química , Biguanidas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Sulfonamidas/química , Sulfonamidas/farmacologia
17.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064890

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.


Assuntos
Benzopiranos/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/química , Domínio Catalítico , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
18.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063139

RESUMO

The concurrent use of oral encorafenib (Braftovi, ENF) and binimetinib (Mektovi, BNB) is a combination anticancer therapy approved by the United States Food and Drug Administration (USFDA) for patients with BRAFV600E/V600K mutations suffering from metastatic or unresectable melanoma. Metabolism is considered one of the main pathways of drug elimination from the body (responsible for elimination of about 75% of known drugs), it is important to understand and study drug metabolic stability. Metabolically unstable compounds are not good as they required repetitive dosages during therapy, while very stable drugs may result in increasing the risk of adverse drug reactions. Metabolic stability of compounds could be examined using in vitro or in silico experiments. First, in silico metabolic vulnerability for ENF and BNB was investigated using the StarDrop WhichP450 module to confirm the lability of the drugs under study to liver metabolism. Second, we established an LC-MS/MS method for the simultaneous quantification of ENF and BNB applied to metabolic stability assessment. Third, in silico toxicity assessment of ENF and BNB was performed using the StarDrop DEREK module. Chromatographic separation of ENF, BNB, and avitinib (an internal standard) was achieved using an isocratic mobile phase on a Hypersil BDS C18 column. The linear range for ENF and BNB in the human liver microsome (HLM) matrix was 5-500 ng/mL (R2 ≥ 0.999). The metabolic stabilities were calculated using intrinsic clearance and in vitro half-life. Furthermore, ENF and BNB did not significantly influence each other's metabolic stability or metabolic disposition when used concurrently. These results indicate that ENF and BNB will slowly bioaccumulate after multiple doses.


Assuntos
Antineoplásicos/análise , Benzimidazóis/análise , Benzimidazóis/metabolismo , Carbamatos/análise , Carbamatos/metabolismo , Aprovação de Drogas , Sulfonamidas/análise , Sulfonamidas/metabolismo , Espectrometria de Massas em Tandem , Benzimidazóis/química , Calibragem , Carbamatos/química , Cromatografia Líquida , Simulação por Computador , Estabilidade de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Controle de Qualidade , Reprodutibilidade dos Testes , Sulfonamidas/química , Estados Unidos , United States Food and Drug Administration
19.
ACS Chem Biol ; 16(6): 982-990, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34003636

RESUMO

Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonamidas/farmacologia , Anidrase Carbônica II/metabolismo , Linhagem Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Furanos/química , Humanos , Indenos/química , Inflamassomos/metabolismo , Macrófagos/metabolismo , Modelos Moleculares , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteômica , Sulfonamidas/química
20.
Cell Biochem Biophys ; 79(2): 189-200, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33954893

RESUMO

Breast cancer resistance protein (ABCG2) is a human ATP-binding cassette (ABC) that plays a paramount role in multidrug resistance (MDR) in cancer therapy. The discovery of ABCG2 inhibitors could assist in designing unprecedented therapeutic strategies for cancer treatment. There is as yet no approved drug targeting ABCG2, although a large number of drug candidates have been clinically investigated. In this work, binding affinities of 181 drug candidates in clinical-trial or investigational stages as ABCG2 inhibitors were inspected using in silico techniques. Based on available experimental data, the performance of AutoDock4.2.6 software was first validated to predict the inhibitor-ABCG2 binding mode and affinity. Combined molecular docking calculations and molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations, were then performed to filter out the studied drug candidates. From the estimated docking scores and MM-GBSA binding energies, six auspicious drug candidates-namely, pibrentasvir, venetoclax, ledipasvir, avatrombopag, cobicistat, and revefenacin-exhibited auspicious binding energies with value < -70.0 kcal/mol. Interestingly, pibrentasvir, venetoclax, and ledipasvir were observed to show even higher binding affinities with the ABCG2 transporter with binding energies of < -80.0 kcal/mol over long MD simulations of 100 ns. The stabilities of these three promising candidates in complex with ABCG2 transporter were demonstrated by their energetics and structural analyses throughout the 100 ns MD simulations. The current study throws new light on pibrentasvir, venetoclax, and ledipasvir as curative options for multidrug resistant cancers by inhibiting ABCG2 transporter.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Benzimidazóis/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Fluorenos/química , Proteínas de Neoplasias/antagonistas & inibidores , Pirrolidinas/química , Sulfonamidas/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzimidazóis/metabolismo , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Bases de Dados de Compostos Químicos , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluorenos/metabolismo , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Pirrolidinas/metabolismo , Sulfonamidas/metabolismo , Termodinâmica
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