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1.
Biochim Biophys Acta Gen Subj ; 1865(1): 129773, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33132199

RESUMO

BACKGROUND: Quinazolines 1 to 6, with an aromatic or aryl-vinyl substituent in position 2 are selected with the aim to compare their structures and biological activity. The selection includes a natural alkaloid, schizocommunin, and the synthetic 2-(2'-quinolyl)-3H-quinazolin-4-one, known to interact with guanine-quadruplex dependent enzymes, respectively telomerase and topoisomerase. METHODS: Breast cancer cells of the MDA cell line have been used to study the bioactivity of the tested compounds by the method of Comet Assay and FACS analyses. We model observed effects assuming stacking interactions of studied heterocycles with a naked skeleton of G-quadruplex, consisting of guanine quartet layers and potassium ions. Interaction energies are computed using a dispersion corrected density functional theory method, and an electron-correlated molecular orbital theory method. RESULTS: Selected compounds do not remarkably delay nor change the dynamics of cellular progression through the cell cycle phases, while changing significantly cell morphology. Our computational models quantify structural effects on heterocyclic G4-complex stabilization energies, which directly correlate with observed biological activity. CONCLUSION: Our computational model of G-quadruplexes is an acceptable tool for the study of interaction energies of G-quadruplexes and heterocyclic ligands, predicting, and allowing design of novel structures. GENERAL SIGNIFICANCE: Genotoxicity of quinazolin-4-one analogues on human breast cancer cells is not related to molecular metabolism but rather to their interference with G-quadruplex regulatory mechanisms. Computed stabilization energies of heterocyclic ligand complexes of G-quadruplexes might be useful in the prediction of novel telomerase / helicase, topoisomerase and NA polymerase dependent drugs.


Assuntos
Quadruplex G/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Humanos , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Quinazolinonas/química , Quinazolinonas/farmacologia , Telômero/química
2.
J Mol Model ; 26(12): 341, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33200284

RESUMO

HER-2 type breast cancer is one of the most aggressive malignancies found in women. Tucatinib is recently developed and approved as a potential medicine to fight this disease. In this manuscript, we present the gross structural features of this compound and its reactivity and wave function properties using computational simulations. Density functional theory was used to optimise the ground state geometry of the molecule and molecular docking was used to predict biological activity. As the electrons interact with electromagnetic radiations, electronic excitations between different energy levels are analysed in detail using time-dependent density functional theory. Various intermolecular and intermolecular interactions are analysed and reaction sites for attacking electrophiles and nucleophiles identified. Information entropy calculations show that the compound is inherently stable. Docking with COVID-19 proteins show docking score of - 9.42, - 8.93, - 8.45 and - 8.32 kcal/mol respectively indicating high interaction between the drug and proteins. Hence, this is an ideal candidate to study repurposing of existing drugs to combat the pandemic.


Assuntos
Antineoplásicos/química , Antivirais/química , Betacoronavirus/química , Elétrons , Oxazóis/química , Inibidores de Proteases/química , Piridinas/química , Quinazolinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antineoplásicos/metabolismo , Antivirais/metabolismo , Betacoronavirus/enzimologia , Sítios de Ligação , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Reposicionamento de Medicamentos , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxazóis/metabolismo , Inibidores de Proteases/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Piridinas/metabolismo , Teoria Quântica , Quinazolinas/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
3.
Nucleic Acids Res ; 48(20): 11259-11269, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33080032

RESUMO

A single G-quadruplex forming sequence from the human telomere can adopt six distinct topologies that are inter-convertible under physiological conditions. This presents challenges to design ligands that show selectivity and specificity towards a particular conformation. Additional complexity is introduced in differentiating multimeric G-quadruplexes over monomeric species, which would be able to form in the single-stranded 3' ends of telomeres. A few ligands have been reported that bind to dimeric quadruplexes, but their preclinical pharmacological evaluation is limited. Using multidisciplinary approaches, we identified a novel quinoline core ligand, BMPQ-1, which bound to human telomeric G-quadruplex multimers over monomeric G-quadruplexes with high selectivity, and induced the formation of G-quadruplex DNA along with the related DNA damage response at the telomere. BMPQ-1 reduced tumor cell proliferation with an IC50 of ∼1.0 µM and decreased tumor growth rate in mouse by half. Biophysical analysis using smFRET identified a mixture of multiple conformations coexisting for dimeric G-quadruplexes in solution. Here, we showed that the titration of BMPQ-1 shifted the conformational ensemble of multimeric G-quadruplexes towards (3+1) hybrid-2 topology, which became more pronounced as further G-quadruplex units are added.


Assuntos
Proliferação de Células/efeitos dos fármacos , Quadruplex G , Conformação de Ácido Nucleico , Quinazolinas/química , Quinazolinas/farmacologia , Telômero/química , Telômero/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dicroísmo Circular , Dano ao DNA , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração Inibidora 50 , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Quinazolinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Molecules ; 25(17)2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32842606

RESUMO

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Catepsina L/química , Compostos Fitoquímicos/química , Inibidores de Proteases/química , Receptores Virais/química , Serina Endopeptidases/química , Sequência de Aminoácidos , Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Sítios de Ligação , Catepsina L/antagonistas & inibidores , Catepsina L/genética , Catepsina L/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Cumarínicos/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Expressão Gênica , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Índia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Monossacarídeos/química , Monossacarídeos/isolamento & purificação , Monossacarídeos/farmacologia , Pandemias , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Quinazolinas/química , Quinazolinas/isolamento & purificação , Quinazolinas/farmacologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/genética , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Termodinâmica , Internalização do Vírus/efeitos dos fármacos
5.
Top Curr Chem (Cham) ; 378(4-5): 44, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32776212

RESUMO

Perimidines are versatile scaffolds and a fascinating class of N-heterocycles that have evolved significantly in recent years due to their immense applications in life sciences, medical sciences, and industrial chemistry. Their ability of molecular interaction with different proteins, complex formation with metals, and distinct behavior in various ranges of light makes them more appealing and challenging for future scientists. Various novel technologies have been developed for the selective synthesis of perimidines and their conjugated derivatives. These methods extend to the preparation of different bioactive and industrially applicable molecules. This review aims to present the most recent advancements in perimidine synthesis under varied conditions like MW radiation, ultrasound, and grinding using different catalysts such as ionic liquids, acid, metal, and nanocatalyst and also under green environments like catalyst and solvent-free synthesis. The applications of perimidine derivatives in drug discovery, polymer chemistry, photo sensors, dye industries, and catalytic activity in organic synthesis are discussed in this survey. This article is expected to be a systematic, authoritative, and critical review on the chemistry of perimidines that compiles most of the state-of-art innovation in this area.


Assuntos
Quinazolinas/síntese química , Descoberta de Drogas , Estrutura Molecular , Quinazolinas/química , Ondas Ultrassônicas
6.
J Med Chem ; 63(17): 9828-9837, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32794708

RESUMO

Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 Å movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Inibidores da Fosfodiesterase 5/metabolismo , Quinazolinas/metabolismo , Sítio Alostérico , Sequência de Aminoácidos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Descoberta de Drogas , Masculino , Camundongos , Simulação de Acoplamento Molecular , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacocinética , Ligação Proteica , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos Sprague-Dawley , Alinhamento de Sequência , Relação Estrutura-Atividade
7.
Biochem Pharmacol ; 180: 114132, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32622666

RESUMO

Acute kidney injury (AKI), characterized by a rapid decline in renal function, is triggered by an acute inflammatory response that leads to kidney damage. An effective treatment for AKI is lacking. Using in vitro and in vivo AKI models, our laboratory has identified a series of anti-inflammatory molecules and their derivatives. In the current study, we identified the protective role of rutaecarpine (Ru) on renal tubules. We obtained a series of 3-aromatic sulphonamide-substituted Ru derivatives exhibiting enhanced renoprotective and anti-inflammatory function. We identified Compound-6c(Cpd-6c) as having the best activity and examined its protective effect against cisplatin nephropathy both in vivo and in vitro in cisplatin-stimulated tubular epithelial cells (TECs). Our results showed that Cpd-6c restored renal function more effectively than Ru, as evidenced by reduced blood urea nitrogen and serum creatinine levels in mice. Cpd-6c alleviated tubular injury, as shown by PAS staining and molecular analysis of kidney injury molecule-1 (KIM-1), with both prevention and treatment protocols in cisplatin-treated mice. Moreover, Cpd-6c decreased kidney inflammation, oxidative stress and programmed cell death. These results have also been confirmed in cisplatin-treated TECs. Using web-prediction algorithms, molecular docking, and cellular thermal shift assay (CETSA), we identified phosphodiesterase 4B (PDE4B) as a Cpd-6c target. In addition, we firstly found that PDE4B was up-regulated significantly in the serum of AKI patients. After identifying the function of PDE4B in cisplatin-treated tubular epithelial cells by siRNA transfection or PDE4 inhibitor rolipram, we showed that Cpd-6c treatment did not protect against cisplatin-induced injury in PDE4B knockdown TECs, thus indicating that Cpd-6c exerts its renoprotective and anti-oxidative effects via the PDE4B-dependent pathway. Collectively, Cpd-6c might serve as a potential therapeutic agent for AKI and PDE4B may be highly involved in the initiation and progression of AKI.


Assuntos
Lesão Renal Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Cisplatino/efeitos adversos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Alcaloides Indólicos/farmacologia , Túbulos Renais/efeitos dos fármacos , Quinazolinas/farmacologia , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/patologia , Animais , Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Humanos , Alcaloides Indólicos/química , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Ligação Proteica , Quinazolinas/química
8.
J Agric Food Chem ; 68(20): 5586-5595, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32357298

RESUMO

Plant diseases seriously affect the yield and quality of crops and are difficult to control. Tryptanthrin and its derivatives (tryptanthrins) were synthesized and evaluated for their antiviral activities and fungicidal activities. We found that tryptanthrins have good antiviral activities against tobacco mosaic virus (TMV) for the first time. Most of the tryptanthrins showed higher anti-TMV activities than that of ribavirin (inhibitory rates of 40, 37, and 38% at 500 µg/mL for inactivation, curative, and protection activities in vivo, respectively). Compound 3n (inhibitory rates of 52, 49, and 54% at 500 µg/mL for inactivation, curative, and protection activities in vivo, respectively) and compound 14 (inhibitory rates of 51, 48, and 53% at 500 µg/mL for inactivation, curative, and protection activities in vivo, respectively) emerged as new antiviral lead compounds with excellent antiviral activities. Compound 16 was selected for further antiviral mechanism research, which revealed that compound 16 could inhibit virus assembly by decomposing 20S coat protein (CP) disk. Molecular docking results showed that compounds 3n and 14, which have higher antiviral activities in vivo than that of compound 16, do show stronger interaction with TMV CP. Further fungicidal activity tests showed that tryptanthrins displayed broad-spectrum fungicidal activities, especially for compound 16. These compounds showed good selectivity to Physalospora piricola. In the current study, a small molecular library of tryptanthrin was constructed and the bioactivity spectrum of these compounds was broadened, which lays a foundation for their application in plant protection.


Assuntos
Antivirais/química , Antivirais/farmacologia , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Quinazolinas/farmacologia , Desenho de Fármacos , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Estrutura Molecular , Doenças das Plantas/microbiologia , Doenças das Plantas/virologia , Quinazolinas/química , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Vírus do Mosaico do Tabaco/crescimento & desenvolvimento
9.
J Agric Food Chem ; 68(18): 5059-5067, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32286826

RESUMO

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been identified as one of the most significant targets in herbicide discovery for resistant weed control. In a continuing effort to discover potent novel HPPD inhibitors, we adopted a ring-expansion strategy to design a series of novel pyrazole-quinazoline-2,4-dione hybrids based on the previously discovered pyrazole-isoindoline-1,3-dione scaffold. One compound, 3-(2-chlorophenyl)-6-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4-carbonyl)-1,5-dimethylquinazoline-2,4(1H,3H)-dione (9bj), displayed excellent potency against AtHPPD, with an IC50 value of 84 nM, which is approximately 16-fold more potent than pyrasulfotole (IC50 = 1359 nM) and 2.7-fold more potent than mesotrione (IC50 = 226 nM). Furthermore, the co-crystal structure of the AtHPPD-9bj complex (PDB ID 6LGT) was determined at a resolution of 1.75 Å. Similar to the existing HPPD inhibitors, compound 9bj formed a bidentate chelating interaction with the metal ion and a π-π stacking interaction with Phe381 and Phe424. In contrast, o-chlorophenyl at the N3 position of quinazoline-2,4-dione with a double conformation was surrounded by hydrophobic residues (Met335, Leu368, Leu427, Phe424, Phe392, and Phe381). Remarkably, the greenhouse assay indicated that most compounds displayed excellent herbicidal activity (complete inhibition) against at least one of the tested weeds at the application rate of 150 g of active ingredient (ai)/ha. Most promisingly, compounds 9aj and 9bi not only exhibited prominent weed control effects with a broad spectrum but also showed very good crop safety to cotton, peanuts, and corn at the dose of 150 g of ai/ha.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Inibidores Enzimáticos/química , Proteínas de Plantas/antagonistas & inibidores , Plantas Daninhas/enzimologia , Pirazóis/química , Quinazolinas/química , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Inibidores Enzimáticos/farmacologia , Herbicidas/química , Herbicidas/farmacologia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Daninhas/química , Plantas Daninhas/efeitos dos fármacos , Pirazóis/farmacologia , Quinazolinas/farmacologia , Relação Estrutura-Atividade , Controle de Plantas Daninhas
10.
J Enzyme Inhib Med Chem ; 35(1): 1110-1115, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32338093

RESUMO

A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC50= 106 nM) with excellent selectivity profiles over 36 other protein kinases including cKit and FMS kinase. Compound 7d was also active in FLT-ITD, with an IC50 value of 301 nM, and other FLT3 mutants showing potential as an AML therapeutics.


Assuntos
Descoberta de Drogas , Isoxazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Tirosina Quinase 3 Semelhante a fms/metabolismo
11.
J Biol Chem ; 295(21): 7289-7300, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32284327

RESUMO

N-Acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) (EC 3.1.4.4) catalyzes the final step in the biosynthesis of N-acyl-ethanolamides. Reduced NAPE-PLD expression and activity may contribute to obesity and inflammation, but a lack of effective NAPE-PLD inhibitors has been a major obstacle to elucidating the role of NAPE-PLD and N-acyl-ethanolamide biosynthesis in these processes. The endogenous bile acid lithocholic acid (LCA) inhibits NAPE-PLD activity (with an IC50 of 68 µm), but LCA is also a highly potent ligand for TGR5 (EC50 0.52 µm). Recently, the first selective small-molecule inhibitor of NAPE-PLD, ARN19874, has been reported (having an IC50 of 34 µm). To identify more potent inhibitors of NAPE-PLD, here we used a quenched fluorescent NAPE analog, PED-A1, as a substrate for recombinant mouse Nape-pld to screen a panel of bile acids and a library of experimental compounds (the Spectrum Collection). Muricholic acids and several other bile acids inhibited Nape-pld with potency similar to that of LCA. We identified 14 potent Nape-pld inhibitors in the Spectrum Collection, with the two most potent (IC50 = ∼2 µm) being symmetrically substituted dichlorophenes, i.e. hexachlorophene and bithionol. Structure-activity relationship assays using additional substituted dichlorophenes identified key moieties needed for Nape-pld inhibition. Both hexachlorophene and bithionol exhibited significant selectivity for Nape-pld compared with nontarget lipase activities such as Streptomyces chromofuscus PLD or serum lipase. Both also effectively inhibited NAPE-PLD activity in cultured HEK293 cells. We conclude that symmetrically substituted dichlorophenes potently inhibit NAPE-PLD in cultured cells and have significant selectivity for NAPE-PLD versus other tissue-associated lipases.


Assuntos
Diclorofeno , Inibidores Enzimáticos , Fosfolipase D , Animais , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Bitionol/química , Bitionol/farmacologia , Diclorofeno/química , Diclorofeno/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Células HEK293 , Hexaclorofeno/química , Hexaclorofeno/farmacologia , Humanos , Camundongos , Fosfolipase D/antagonistas & inibidores , Fosfolipase D/química , Fosfolipase D/metabolismo , Quinazolinas/química , Quinazolinas/farmacologia , Streptomyces/enzimologia , Sulfonamidas/química , Sulfonamidas/farmacologia
12.
Biomolecules ; 10(3)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120929

RESUMO

Strobilanthes cusia (Nees) Kuntze is a Chinese herbal medicine used in the treatment of respiratory virus infections. The methanol extract of S. cusia leaf contains chemical components such as ß-sitosterol, indirubin, tryptanthrin, betulin, indigodole A, and indigodole B that have diverse biological activities. However, the antiviral action of S. cusia leaf and its components against human coronavirus remains to be elucidated. Human coronavirus NL63 infection is frequent among immunocompromised individuals, young children, and in the elderly. This study investigated the anti-Human coronavirus NL63 (HCoV-NL63) activity of the methanol extract of S. cusia leaf and its major components. The methanol extract of S. cusia leaf effectively inhibited the cytopathic effect (CPE) and virus yield (IC50 = 0.64 µg/mL) in HCoV-NL63-infected cells. Moreover, this extract potently inhibited the HCoV-NL63 infection in a concentration-dependent manner. Among the six components identified in the methanol extract of S. cusia leaf, tryptanthrin and indigodole B (5aR-ethyltryptanthrin) exhibited potent antiviral activity in reducing the CPE and progeny virus production. The IC50 values against virus yield were 1.52 µM and 2.60 µM for tryptanthrin and indigodole B, respectively. Different modes of time-of-addition/removal assay indicated that tryptanthrin prevented the early and late stages of HCoV-NL63 replication, particularly by blocking viral RNA genome synthesis and papain-like protease 2 activity. Notably, tryptanthrin (IC50 = 0.06 µM) and indigodole B (IC50 = 2.09 µM) exhibited strong virucidal activity as well. This study identified tryptanthrin as the key active component of S. cusia leaf methanol extract that acted against HCoV-NL63 in a cell-type independent manner. The results specify that tryptanthrin possesses antiviral potential against HCoV-NL63 infection.


Assuntos
Acanthaceae/química , Antivirais/farmacologia , Coronavirus Humano NL63/fisiologia , Quinazolinas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Acanthaceae/metabolismo , Animais , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Coronavirus Humano NL63/isolamento & purificação , Humanos , Macaca mulatta , Medicina Tradicional Chinesa , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Quinazolinas/química , Quinazolinas/isolamento & purificação , Quinazolinas/uso terapêutico
13.
Int J Med Sci ; 17(3): 390-402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32132874

RESUMO

Background: Combination chemotherapy plays an important role in the clinical therapy of non-small cell lung cancer (NSCLC). However, the pharmacokinetic differences between drugs are an insurmountable barrier in traditional treatment. For the synergistic therapy of NSCLC, synergistic nanoparticles (EDS NPs) loaded with both an EGFR inhibitor and doxorubicin (DOX) were designed and prepared. Methods: Erlotinib, apatinib and icotinib were evaluated for optimal combination with DOX in treatment of NSCLC via CCK-8 assay. Then the cationic amphipathic starch (CSaSt) and hyaluronic acid (HA) were applied to coencapsulate DOX and EGFR inhibitor to form the EDS NPs. EDS NPs were evaluated in NSCLC cell lines (A549, NCI-H1975 and PC9) and NSCLC xenograft mouse models. Results: Icotinib was found to be the optimal synergistic drug in combination with DOX in the tested. Subsequently, icotinib and DOX were coencapsulated in the NPs. EDS NPs were roughly spherical with an average size of 65.7±6.2 nm and possessed stable loading and releasing properties. In the in vitro investigation, EDS NPs could efficiently deliver payloads into cells, exhibited cytotoxicity and produced strong anti-migration properties. In vivo hypotoxicity was confirmed by acute toxicity and hemolytic assays. The in vivo distribution showed that EDS NPs could enhance accumulation in tumors and decrease nonspecific accumulation in normal organs. EDS NPs significantly promoted the in vivo synergistic effects of icotinib and DOX in the mouse model. Conclusions: The study suggests that EDS NPs possess noteworthy potential for development as therapeutics for NSCLC clinical chemotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Éteres de Coroa/química , Doxorrubicina/química , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Quinazolinas/química , Células A549 , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Éteres de Coroa/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quinazolinas/uso terapêutico
14.
J Mol Histol ; 51(2): 191-197, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32219645

RESUMO

EGFR signaling plays important roles in the development of eccrine sweat glands. We previously demonstrate that Matrigel induces eccrine sweat gland cells to reconstruct the three-dimensional (3D) structures of eccrine sweat glands, but the mechanisms are still unknown. In the study, eccrine sweat gland cells were cultured within a 3D Matrigel, and EGFR inhibitor AG1478, or MEK1/2 inhibitor U0126, were added to the medium respectively. The morphology of the 3D-reconstructed eccrine sweat gland-like structures was observed, the localization of phospho-EGFR was detected, and protein levels of EGFR, phospho-EGFR, phospho-JAK, phospho-AKT and phospho-ERK were examined. The results showed that cells treatment with AG1478 from Day 0 of 3D cultures blocked formation of spheroid-like structures. AG1478 administration caused reduced phospho-EGFR, concomitant with downregulation of phospho-ERK1/2, but not phospho-JAK or phospho-AKT. Phospho-EGFR and phospho-ERK were reduced, and only a small number of 3D-structures were formed following treatment with U0126. We conclude that EGFR plays important roles in Matrigel-induced 3D structures of eccrine sweat gland-like structures, and ERK1/2 signaling is responsible, at least in part, for the effect of EGFR.


Assuntos
Glândulas Écrinas/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinazolinas/farmacologia , Tirfostinas/farmacologia , Técnicas de Cultura de Células , Células Cultivadas , Colágeno , Combinação de Medicamentos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Janus Quinases/metabolismo , Laminina , Fosforilação , Proteoglicanas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/química , Transdução de Sinais , Tirfostinas/química
15.
Molecules ; 25(6)2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32183140

RESUMO

Malaria, affecting all continents, remains one of the life-threatening diseases introduced by parasites that are transmitted to humans through the bites of infected Anopheles mosquitoes. Although insecticides are currently used to reduce malaria transmission, their safety concern for living systems, as well as the environment, is a growing problem. Therefore, the discovery of novel, less toxic, and environmentally safe molecules to effectively combat the control of these vectors is in high demand. In order to identify new potential larvicidal agents, a series of 2-aryl-1,2-dihydroquinazolin-4-one derivatives were synthesized and evaluated for their larvicidal activity against Anopheles arabiensis. The in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the compounds were also investigated and most of the derivatives possessed a favorable ADMET profile. Computational modeling studies of the title compounds demonstrated a favorable binding interaction against the acetylcholinesterase enzyme molecular target. Thus, 2-aryl-1,2-dihydroquinazolin-4-ones were identified as a novel class of Anopheles arabiensis insecticides which can be used as lead molecules for the further development of more potent and safer larvicidal agents for treating malaria.


Assuntos
Anopheles/efeitos dos fármacos , Simulação por Computador , Inseticidas/toxicidade , Malária/parasitologia , Mosquitos Vetores/efeitos dos fármacos , Quinazolinas/toxicidade , Animais , Cristalografia por Raios X , Inseticidas/síntese química , Inseticidas/química , Larva/efeitos dos fármacos , Modelos Moleculares , Conformação Molecular , Quinazolinas/síntese química , Quinazolinas/química , Estereoisomerismo
16.
Molecules ; 25(6)2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32183146

RESUMO

Evodiamine (EVO) is an indoloquinazoline alkaloid that exerts its various anti-oncogenic actions by blocking phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), c-Met, and nuclear factor kappa B (NF-κB) signaling pathways, thus leading to apoptosis of tumor cells. We investigated the ability of EVO to affect hepatocyte growth factor (HGF)-induced c-Met/Src/STAT3 activation cascades in castration-resistant prostate cancer (CRPC). First, we noted that EVO showed cytotoxicity and anti-proliferation activities in PC-3 and DU145 cells. Next, we found that EVO markedly inhibited HGF-induced c-Met/Src/STAT3 phosphorylation and impaired the nuclear translocation of STAT3 protein. Then, we noted that EVO arrested the cell cycle, caused apoptosis, and downregulated the expression of various carcinogenic markers such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), cyclin D1, cyclooxygenase 2 (COX-2), survivin, vascular endothelial growth factor (VEGF), and matrix metallopeptidases 9 (MMP-9). Moreover, it was observed that in cPC-3 and DU145 cells transfected with c-Met small interfering RNA (siRNA), Src/STAT3 activation was also mitigated and led to a decrease in EVO-induced apoptotic cell death. According to our results, EVO can abrogate the activation of the c-Met/Src/STAT3 signaling axis and thus plays a role as a robust suppressor of tumor cell survival, proliferation, and angiogenesis.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinazolinas/farmacologia , Transdução de Sinais , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Dano ao DNA/genética , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Masculino , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/genética , Quinazolinas/química , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismo
17.
Eur J Med Chem ; 192: 112185, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32145644

RESUMO

Over the past decade, we described a novel tumour targeted approach that sought to design "combi-molecules" to hit two distinct targets in tumour cells. Here, to generate small combi-molecules with strong DNA damaging potential while retaining EGFR inhibitory potency, we developed the first synthetic strategy to access the 6-N, N-disubstituted quinazoline scaffold and designed JS61 to possess a nitrogen mustard function directly attached to the 6-position of the quinazoline ring. We compared its biological activity with that of structures containing either a hemi mustard or a non-alkylating substituent. Surprisingly, the results showed that JS61, while capable of inducing strong DNA damage, exhibited moderate EGFR inhibitory potency. In contrast, "combi-molecules" with no bulky substituent at the N-6 position (e.g. ZR2002 and JS84) showed stronger EGFR and growth inhibitory potency than JS61 in a panel of lung cancer cells. To rationalize these results, X-ray crystallography and molecular modeling studies were undertaken, and the data obtained indicated that bulkiness of the 6-N,N-disubstituted moieties hinder its binding to the ATP site and affects binding reversibility.


Assuntos
Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Quinazolinas/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Bovinos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Biochem Pharmacol ; 174: 113834, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027884

RESUMO

Acid-sensing ion channels (ASICs) are voltage-independent cation channels that detect decreases in extracellular pH. Dysregulation of ASICs underpins a number of pathologies. Of particular interest is ASIC3, which is recognised as a key sensor of acid-induced pain and is important in the establishment of pain arising from inflammatory conditions, such as rheumatoid arthritis. Thus, the identification of new ASIC3 modulators and the mechanistic understanding of how these compounds modulate ASIC3 could be important for the development of new strategies to counteract the detrimental effects of dysregulated ASIC3 activity in inflammation. Here, we report the identification of novel ASIC3 modulators based on the ASIC3 agonist, 2-guanidine-4-methylquinazoline (GMQ). Through a GMQ-guided in silico screening of Food and Drug administration (FDA)-approved drugs, 5 compounds were selected and tested for their modulation of rat ASIC3 (rASIC3) using whole-cell patch-clamp electrophysiology. Of the chosen drugs, guanabenz (GBZ), an α2-adrenoceptor agonist, produced similar effects to GMQ on rASIC3, activating the channel at physiological pH (pH 7.4) and potentiating its response to mild acidic (pH 7) stimuli. Sephin1, a GBZ derivative that lacks α2-adrenoceptor activity, has been proposed to act as a selective inhibitor of a regulatory subunit of the stress-induced protein phosphatase 1 (PPP1R15A) with promising therapeutic potential for the treatment of multiple sclerosis. However, we found that like GBZ, sephin1 activates rASIC3 at pH 7.4 and potentiates its response to acidic stimulation (pH 7), i.e. sephin1 is a novel modulator of rASIC3. Furthermore, docking experiments showed that, like GMQ, GBZ and sephin1 likely interact with the nonproton ligand sensor domain of rASIC3. Overall, these data demonstrate the utility of computational analysis for identifying novel ASIC3 modulators, which can be validated with electrophysiological analysis and may lead to the development of better compounds for targeting ASIC3 in the treatment of inflammatory conditions.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Simulação por Computador , Guanabenzo/análogos & derivados , Guanabenzo/metabolismo , Guanidinas/metabolismo , Quinazolinas/metabolismo , Canais Iônicos Sensíveis a Ácido/química , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Guanabenzo/química , Guanabenzo/farmacologia , Guanidinas/química , Guanidinas/farmacologia , Estrutura Secundária de Proteína , Quinazolinas/química , Quinazolinas/farmacologia
19.
Molecules ; 25(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093392

RESUMO

A series of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones were prepared from 2-acylnaphthohydroquinones and 2-aminobenzothiazoles and were evaluated for their in vitro antiproliferative activity. After screening using the MTT reduction assay, their IC50 values were calculated on a panel of cancer cells (T24, DU-145, MCF-7). Current standard anticancer drugs were included as control, and their calculated IC50 values were 7.8 and 23.5 µM for 5-fluorouracil and tamoxifen, respectively. Non-cancer cells (AG1523) were included to assess cancer cell sensitivity and drug selectivity. Four members of the series, with IC50 values from 0.11 to 2.98 µM, were chosen for further assays. The selected quinones were evaluated regarding their effects on cancer cell proliferation (clonogenic assay) and on Hsp90 and poly(ADPribose)polymerase (PARP) protein integrity. The most active compound (i.e., 15) substantially inhibited colony forming unit (CFU) formation at 0.25 µM. In the presence of ascorbate, it induced an oxidative cleavage of Hsp90 but had no effect on PARP protein integrity. In an in vivo animal model, it discreetly increased the mean survival time (m.s.t.) of tumor-bearing mice. In light of these results, compound 15 represents a potential lead-molecule to be further developed.


Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Proteínas de Choque Térmico HSP90 , Proteínas de Neoplasias , Neoplasias Experimentais , Quinazolinas , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ácido Ascórbico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Células MCF-7 , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Enzyme Inhib Med Chem ; 35(1): 598-609, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32009479

RESUMO

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2-13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2-13 with inhibition constants (KIs) ranging from 57.8-740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with KIs between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2-13 with KI values ranging from 7.1 to 93.6 nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (KIs ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Quinazolinas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
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