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1.
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
2.
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
3.
Eur J Med Chem ; 189: 112078, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004937

RESUMO

For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT1 and MT2 ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT1 and MT2, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.


Assuntos
Acetamidas/química , Ftalazinas/química , Quinazolinas/química , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Acetamidas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Células HEK293 , Humanos , Ligantes , Ftalazinas/metabolismo , Quinazolinas/metabolismo , Relação Estrutura-Atividade
4.
Environ Toxicol Pharmacol ; 74: 103310, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837525

RESUMO

We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.


Assuntos
Antineoplásicos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Oxigenases/metabolismo , Piperidinas/metabolismo , Quinazolinas/metabolismo , Animais , Humanos , Microssomos Hepáticos , Oxirredução , Ratos
5.
Environ Toxicol ; 35(4): 507-517, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31804023

RESUMO

Doxorubicin (Dox) is one of the most successful anticancer drugs in use. However, chemoresistance is one of the main limitations that patients face. Therefore, development of new strategies to improve the efficacy of Dox is needed. Marine-derived fungi are especially promising sources of new anticancer compounds. In this work, antitumor activity of crude ethyl extract of the cultures of the marine-derived fungus Neosartorya siamensis KUFA 0017 (NS), combined with Dox, was evaluated in six cancer cell lines. To evaluate possible mechanisms involved in the eventual improvement of Dox's cytotoxicity by NS extract, effects on DNA damage, cell death, ultrastructural modifications, and intracellular accumulation of Dox were assessed. The NS extract demonstrated a significant enhancement of Dox's cytotoxic activity in A549 cells, inducing DNA damage, cell death, and intracellular accumulation of Dox. Additionally, the cytotoxic effect of eight compounds, isolated from this extract, that is, 2,4-dihydroxy-3-methylacetophenone-(C1), nortryptoquivaline-(C2), chevalone C-(C3), tryptoquivaline H-(C4), fiscalin A-(C5), epi-fiscalin-C (C6), epi-neofiscalin A-(C7), and epi-fiscalin A-(C8), alone and combined with Dox was also evaluated in lung cancer cells. The cytotoxic effect of Dox was potentiated by all the isolated compounds (except C1) in A549 cells. Therefore, we concluded that NS extract potentiated cytotoxicity by inhibiting cell proliferation, increasing intracellular accumulation of Dox, and inducing cell death (possibly by an autophagic process). The isolated compounds also enhanced the activity of Dox, supporting the potential of this sort of combination. These data call for further studies to characterize drug interactions and underlying mechanisms.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Produtos Biológicos/farmacologia , Doxorrubicina/farmacologia , Neosartorya/metabolismo , Células A549 , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Humanos , Indóis/isolamento & purificação , Indóis/metabolismo , Indóis/farmacologia , Neoplasias Pulmonares/patologia , Quinazolinas/isolamento & purificação , Quinazolinas/metabolismo , Quinazolinas/farmacologia
6.
Carbohydr Res ; 486: 107832, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622868

RESUMO

Quinazolines were surveyed as biologically relevant moieties against different cancer cell lines, so in the present study, we analyzed novel derivatives as target-oriented chemotherapeutic anti-cancer drugs. A series of 3-substituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 4a-e were synthesized via the reaction of 2-aminobenzoic acid (1) with isothiocyanate derivatives 2a-e. S-alkylation and S-glycosylation were carried via the reaction of 4a-e with alkyl halides and α-glycopyranosyl bromides 7a,b under anhydrous alkaline and glycoside conditions, respectively. The S-alkylated and S-glycosylated structures, and not that of the N-alkylated and N-glycosylated isomers, have been selected for the products. Conformational analysis has been studied by homo- and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The S site of alkylation and glycosylation were determined from the 1H, 13C heteronuclear multiple-quantum coherence (HMQC) experiments. All derivatives were subjected to molecular docking calculations, which selected some derivatives (5n, 8c, 8g, 9c, and 9a) as promising ones based on their excellent binding affinities towards the EGFR tyrosine kinase molecular target. The in vitro cytotoxic activity against MCF-7 and HepG2 cell lines showed effective anti-proliferative activity of the analyzed derivatives with lower IC50 values especially 9a with IC50 = 2.09 and 2.08 µM against MCF-7 and HepG2, respectively, and their treatments were safe against the normal cell line Gingival mesenchymal stem cells (GMSC). Moreover, RT-PCR reaction investigated the apoptotic pathway for the compound 9a, which activated the P53 genes and its related genes. So, further work is recommended for developing it as a chemotherapeutic drug.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Quinazolinas/síntese química , Quinazolinas/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/química , Receptores ErbB/metabolismo , Células Hep G2 , Humanos , Células MCF-7 , Conformação Proteica , Quinazolinas/química , Quinazolinas/metabolismo , Relação Estrutura-Atividade
7.
Bioorg Chem ; 93: 103314, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31590041

RESUMO

A series of pyrazolo[1,5-c]quinazolines as EGFR inhibitors was designed and synthesized by highly efficient and novel multicomponent route involving Pd-catalyzed tandem one-pot four-component reaction. The reaction proceeds with good functional group tolerance under a simple condition with excellent regioselectivity and high efficiency. Target compounds were screened against cancer cell lines MDA-MB-231, A549 and H1299. Of these, 9b and 10b exhibited superior anticancer activity (IC50 < 2.5 µM) to erlotinib and gefitinib. Synthetics were able to inhibit EGFR mediated kinase activity, induced ROS in cancer cells promoting mitochondrial mediated apoptosis via halting cell cycle progression at G1 phase.


Assuntos
Receptores ErbB/antagonistas & inibidores , Paládio/química , Inibidores de Proteínas Quinases/síntese química , Pirazóis/química , Quinazolinas/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Catálise , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/metabolismo , Cloridrato de Erlotinib/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/metabolismo , Pirazóis/farmacologia , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
8.
J Med Chem ; 62(20): 9161-9174, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31580660

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial and rate-limiting step of the kynurenine pathway of tryptophan catabolism, has emerged as a key target in cancer immunotherapy because of its role in enabling cancers to evade the immune system. Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the same reaction and play a potential role in cancer immunotherapy. Starting from our previously discovered tryptanthrin IDO1 inhibitor scaffold, we synthesized novel N-benzyl/aryl substituted tryptanthrin derivatives and evaluated their inhibitory efficacy on IDO1, TDO, and IDO2. Most compounds showed similar high inhibitory activities on both IDO1 and TDO, which were significantly superior over that of IDO2 with magnitude difference. We showed that N-benzyl/aryl substituted tryptanthrin directly interacted with IDO1, TDO, and IDO2, significantly augmented the proliferation of T cells in vitro, blocked the kynurenine pathway, and suppressed tumor growth when administered to LLC and H22 tumor-bearing mice.


Assuntos
Inibidores Enzimáticos/química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Quinazolinas/química , Triptofano Oxigenase/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Relação Estrutura-Atividade , Triptofano Oxigenase/metabolismo
9.
Mol Pharmacol ; 96(5): 609-618, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31471455

RESUMO

In the research field of tubulin-binding agents for the development of anticancer agents, hidden targets are emerging as a problem in understanding the exact mechanisms of actions. The quinazoline derivative 1-(4-methoxyphenyl)-1-(quinazolin-4-yl)ethan-1-ol (PVHD121) has anti-cell proliferative activity and inhibits tubulin polymerization by binding to the colchicine site of tubulin. However, the molecular mechanism of action of PVHD121 in cells remains unclear. Here, we demonstrate that PVHD121 delays mitotic entry and efficiently causes mitotic arrest with spindle checkpoint activation, leading to subsequent cell death. The dominant phenotype induced by PVHD121 was aberrant spindles with robust microtubules and unseparated centrosomes. The microtubules were radially distributed, and their ends appeared to adhere to kinetochores, and not to centrosomes. Extensive inhibition by high concentrations of PVHD121 eliminated all microtubules from cells. PVHD277 [1-(4-methoxyphenyl)-1-(2-morpholinoquinazolin-4-yl)ethan-1-ol], a PVHD121 derivative with fluorescence, tended to localize close to the centrosomes when cells prepared to enter mitosis. Our results show that PVHD121 is an antimitotic agent that selectively disturbs microtubule formation at centrosomes during mitosis. This antimitotic activity can be attributed to the targeting of centrosome maturation in addition to the interference with microtubule dynamics. Due to its unique bioactivity, PVHD121 is a potential tool for studying the molecular biology of mitosis and a potential lead compound for the development of anticancer agents. SIGNIFICANCE STATEMENT: Many tubulin-binding agents have been developed as potential anticancer agents. The aim of this study was to understand the subcellular molecular actions of a quinazoline derivative tubulin-binding agent, 1-(4-methoxyphenyl)-1-(quinazolin-4-yl)ethan-1-ol (PVHD121). As expected from its binding activity to tubulin, PVHD121 caused aberrant spindles and inhibited mitotic progression. However, in addition to tubulin, PVHD121 also targeted an unexpected biomolecule involved in centrosome maturation. Due to targeting the biomolecule just before entering mitosis, PVHD121 preferentially inhibited centrosome-derived microtubules rather than chromosome-derived microtubules during spindle formation. This study not only revealed the molecular action of PVHD121 in cells but also emphasized the importance of considering possible tubulin-independent effects of tubulin-binding agents via hidden targeted biomolecules for future use.


Assuntos
Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antimitóticos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/fisiologia , Colchicina/farmacologia , Células HeLa , Humanos , Mitose/efeitos dos fármacos , Mitose/fisiologia , Fuso Acromático
10.
Bioorg Chem ; 91: 103131, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31377387

RESUMO

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC50 ≤ 1 µM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 µM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC50 = 7.54 µM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.


Assuntos
Antineoplásicos/farmacologia , Quinazolinas/farmacologia , Quinonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinonas/síntese química , Quinonas/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/metabolismo
11.
Bioorg Med Chem ; 27(19): 115035, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31434616

RESUMO

PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC50 values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC50 = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kß and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kß. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC50 values of 0.16 and 0.12 µM. Western blot analysis indicated that A8 could attenuate the AKTS473 phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.


Assuntos
Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Quinazolinas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Quinazolinas/síntese química , Quinazolinas/metabolismo , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 29(17): 2516-2524, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350126

RESUMO

Detailed structure activity relationship of two series of quinazoline EHMT1/EHMT2 inhibitors (UNC0224 and UNC0638) have been elaborated. New and active alternatives are presented for the ubiquitous substitution patterns found in literature for the linker to the lysine mimicking region and the lysine mimic itself. These findings could allow for advancing EHMT1/EHMT2 inhibitors of that type beyond tool compounds by fine-tuning physicochemical properties making these inhibitors more drug-like. .


Assuntos
Inibidores Enzimáticos/química , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular Tumoral , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Lisina/química , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Mutação Puntual , Quinazolinas/química , Quinazolinas/metabolismo , Relação Estrutura-Atividade
13.
J Med Chem ; 62(19): 8873-8879, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31335136

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its molecular pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathology of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivatives as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.


Assuntos
Fosfatidilinositol 3-Quinases/química , Inibidores de Fosfoinositídeo-3 Quinase/química , Quinazolinas/química , Animais , Bleomicina/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Conformação Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Fosforilação/efeitos dos fármacos , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Cells ; 8(5)2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121852

RESUMO

The 18 kDa translocator protein (TSPO) ligands 2-Cl-MGV-1 and MGV-1 can attenuate cell death of astrocyte-like cells (U118MG) and induce differentiation of neuronal progenitor cells (PC-12). Lipopolysaccharide (LPS) is a bacterial membrane endotoxin that activates cellular inflammatory pathways by releasing pro-inflammatory molecules, including cytokines and chemokines. The aim of the present study was to assess the immuno-modulatory effect of TSPO ligands in activated microglial cells. We demonstrated that the TSPO ligands 2-Cl-MGV-1 and MGV-1 can prevent LPS-induced activation of microglia (BV-2 cell line). Co-treatment of LPS (100 ng/mL) with these TSPO ligands (final concentration- 25 µM) reduces significantly the LPS-induced release of interleukin-6 (IL-6) from 16.9-fold to 2.5-fold, IL-ß from 8.3-fold to 1.6-fold, interferon-γ from 16.0-fold to 2.2-fold, and tumor necrosis factor-α from 16.4-fold to 1.8-fold. This anti-inflammatory activity seems to be achieved by inhibition of NF-κB p65 activation. Assessment of initiation of ROS generation and cell metabolism shows significant protective effects of these two novel TSPO ligands. The IL-10 and IL-13 levels were not affected by any of the TSPO ligands. Thus, it appears that the ligands suppress the LPS-induced activation of some inflammatory responses of microglia. Such immunomodulatory effects may be relevant to the pharmacotherapy of neuro-inflammatory diseases.


Assuntos
Carbamatos/farmacologia , Citocinas/metabolismo , Inflamação/imunologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Quinazolinas/farmacologia , Receptores de GABA/metabolismo , Animais , Carbamatos/metabolismo , Linhagem Celular , Inflamação/induzido quimicamente , Ligantes , Lipopolissacarídeos/química , Microglia/citologia , Quinazolinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição RelA/metabolismo
15.
J Biol Chem ; 294(27): 10428-10437, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31118272

RESUMO

RET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein-tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain-nintedanib complex to 1.87 Å resolution and a RET(G810A) kinase domain crystal structure to 1.99 Å resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma. Drug-sensitivity profiling of RET(L881V) revealed that it remains sensitive to nintedanib. The RET-nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of nintedanib, providing a structural basis for explaining that the p.L730V mutation identified in nine independently isolated cell lines resistant to nintedanib. Comparisons of RET-nintedanib, RET(G810A), and RET-vandetanib crystal structures suggested that the solvent-front Ala-810 makes hydrophobic contacts with a methyl group and aniline in nintedanib and blocks water access to two oxygen atoms of vandetanib, resulting in an energetic penalty for burying polar groups. Of note, even though the p.L881V mutation did not affect sensitivity to nintedanib, RET(L881V) was resistant to nintedanib analogs lacking a phenyl group. These results provide structural insights into resistance of RET mutants against the TKIs nintedanib and vandetanib.


Assuntos
Indóis/química , Piperidinas/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-ret/química , Quinazolinas/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Piperidinas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Quinazolinas/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética
16.
Eur J Med Chem ; 176: 11-20, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091477

RESUMO

A novel series of dihydroquinazolin-2-amine derivatives were synthesized and evaluated for their anti-HIV-1 activity in MT-4 cell cultures. All of the molecules were active against wild-type HIV-1 with EC50 values ranging from 0.61 µM to 0.84 nM. The most potent inhibitor, compound 4b, had an EC50 value of 0.84 nM against HIV-1 strain IIIB, and thus was more active than the reference drugs efavirenz and etravirine. Moreover, most of the compounds maintained high activity (low-micromolar EC50 values) against strains bearing the reverse transcriptase (RT) E138K mutation. Compound 4b had EC50 values of 3.5 nM and 66 nM against non-nucleoside reverse transcriptase inhibitor-resistant strains bearing the RT E138K and RES056 mutations. In enzyme activity assays, compound 4b exhibited an IC50 value of 10 nM against HIV-1 RT. Preliminary SARs and molecular docking studies provide valuable insights for further optimization.


Assuntos
Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Quinazolinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Aminas/síntese química , Aminas/metabolismo , Aminas/toxicidade , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/toxicidade , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-Atividade
17.
Bioorg Med Chem ; 27(10): 2083-2089, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30967303

RESUMO

New pyrido[3,4-g]quinazoline derivatives were prepared and evaluated for their inhibitory potency toward 5 protein kinases (CLK1, DYRK1A, GSK3, CDK5, CK1). A related pyrido[4,3-h]quinazoline scaffold with an angular structure was also synthesized and its potency against the same protein kinase panel was compared to the analogous pyrido[3,4-g]quinazoline. Best results were obtained for 10-nitropyrido[3,4-g]quinazoline 4 toward CLK1 with nanomolar activities.


Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Piridinas/química , Quinazolinas/química , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Proteínas Quinases/química , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/metabolismo , Relação Estrutura-Atividade
18.
J Med Chem ; 62(9): 4772-4778, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-30973735

RESUMO

We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect.


Assuntos
Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Aminoquinolinas/síntese química , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cordoma/tratamento farmacológico , Desenho de Fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/farmacologia
19.
Bioorg Chem ; 88: 102916, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31026719

RESUMO

Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Dioxanos/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinazolinas/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dioxanos/síntese química , Dioxanos/metabolismo , Feminino , Humanos , Ligação de Hidrogênio , Camundongos SCID , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinazolinas/síntese química , Quinazolinas/metabolismo , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Appl Microbiol Biotechnol ; 103(9): 3773-3781, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30863875

RESUMO

In nature, cyclic dipeptide prenyltransferases catalyze regioselective Friedel-Crafts alkylations of tryptophan-containing cyclic dipeptides. This enzyme class, belonging to the dimethylallyl tryptophan synthase superfamily, is known to be flexible toward aromatic prenyl acceptors, while mostly retaining its typical regioselectivity. Ardeemin fumiquinazoline (FQ) (1), a tryptophan-containing cyclic tripeptide derivative, is assembled in Aspergillus fischeri by the non-ribosomal peptide synthetase ArdA and modified by the prenyltransferase ArdB, leading to the pharmaceutically active hexacyclic ardeemin. Therefore, 1 and its enantiomer ent-ardeemin FQ (2) constitute potential substrates for aromatic prenyltransferases. In this study, we investigated the acceptance of both enantiomers by two cyclic dipeptide C2-prenyltransferases BrePT and FtmPT1 and three C3-prenyltransferases CdpNPT, CdpC3PT, and AnaPT. LC-MS analysis of the incubation mixtures and NMR analysis of the isolated products revealed that the stereochemistry at C11 and C14 in 1 and 2 has a strong influence on their acceptance by these enzymes and the regioselectivity of the prenylation reactions. 1 was very well accepted by BrePT, FtmPT1, and CdpNPT, with C2- or C3-prenylated derivatives as predominant products, which fills the prenylation gaps by tryptophan prenyltransferases reported in a previous study. 2 was a poor substrate for all the enzymes and converted with low regioselectivity and mainly prenylated at C6 and C7 of the indole moiety.


Assuntos
Aspergillus/enzimologia , Dimetilaliltranstransferase/química , Proteínas Fúngicas/química , Alcaloides Indólicos/metabolismo , Quinazolinas/metabolismo , Aspergillus/genética , Aspergillus/metabolismo , Dimetilaliltranstransferase/metabolismo , Dipeptídeos/metabolismo , Proteínas Fúngicas/metabolismo , Alcaloides Indólicos/química , Espectroscopia de Ressonância Magnética , Prenilação , Quinazolinas/química , Estereoisomerismo , Especificidade por Substrato
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