Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 50.608
Filtrar
1.
J Enzyme Inhib Med Chem ; 38(1): 176-191, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36317648

RESUMO

Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle and apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma (HEPG2), larynx cancer (HEP2), lung cancer (H460), colon cancers (HCT116 and Caco2), and hypopharyngeal cancer (FADU), and normal Vero cell lines were used. Compounds 8 and 14 displayed outstanding effects on the investigated cell lines and were further tested for their antioxidant activity in MCF7, H460, FADU, HEP2, HEPG2, HCT116, Caco2, and Vero cells by measuring superoxide dismutase (SOD), malondialdehyde content (MDA), reduced glutathione (GSH), and nitric oxide (NO) content. Besides, Annexin V-FITC apoptosis detection and cell cycle DNA index using the HEPG-2 cell line were established on both compounds as well. Furthermore, compounds 8 and 14 were assessed for their EGFR kinase (Wild and T790M) inhibitory activities, revealing eligible potential. Additionally, molecular docking, ADME, and SAR studies were carried out for the investigated candidates.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Animais , Chlorocebus aethiops , Humanos , Receptores ErbB/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Células Vero , Células CACO-2 , Neoplasias Pulmonares/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Relação Estrutura-Atividade , Mutação , Pirimidinas/farmacologia , Piridinas/farmacologia , Estrutura Molecular
2.
J Enzyme Inhib Med Chem ; 38(1): 203-215, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36382444

RESUMO

The present study aimed to investigate the antitumor effect of simultaneous inhibition of dihydrofolate reductase (DHFR) enzyme. We designed some novel pyrazolo[3,4-d]pyrimidines bearing different amino acid conjugates as efficient antifolate agents attributable to their structural similarity with methotrexate (MTX) and MTX-related antifolates. All compounds were tested to screen their enzymatic inhibition against DHFR compared with the reference drug MTX and for their in vitro antitumor cytotoxicity against six MTX-resistant cancer cell lines. The flow cytometry indicated that the most potent compound 7f arrested MCF-7 cells in the S-phase and induced apoptosis. Western blot for visualisation proved the ability of compound 7f to induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to diminish the expression of antiapoptotic Bcl-2 protein. Molecular modelling studies concluded that compound 7f displayed better binding energy than that of the normal ligand MTX. HIGHLIGHTSNew pyrazolo[3,4-d]pyrimidine derivatives 7a-m which are structurally similar to the classical methotrexate (MTX) and MTX-related antifolates were synthesised as antitumor agents.Novel N-acyl amino acid compound 7f exhibited marked DHFR inhibition activity that are parralel to both the molecular docking results and cytotoxic activity.Compound 7f could induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to diminish the expression of antiapoptotic Bcl-2 protein.All prepared compounds obey Lipinski rule of five except compound 7f.


Assuntos
Antineoplásicos , Neoplasias da Mama , Antagonistas do Ácido Fólico , Humanos , Feminino , Pirimidinas/química , Proteína X Associada a bcl-2 , Metotrexato/farmacologia , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Aminoácidos , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismo , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Caspases/metabolismo
3.
Cancer Lett ; 552: 215981, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341997

RESUMO

Inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzyme for de novo synthesis of pyrimidine nucleotides, have failed in clinical trials for various cancers despite robust efficacy in preclinical animal models. To probe for druggable mediators of DHODH inhibitor resistance, we performed a combination screen with a small molecule library against pancreatic cancer cell lines that are highly resistant to the DHODH inhibitor brequinar (BQ). The screen revealed that CNX-774, a preclinical Bruton tyrosine kinase (BTK) inhibitor, sensitizes resistant cell lines to BQ. Mechanistic studies showed that this effect is independent of BTK and instead results from inhibition of equilibrative nucleoside transporter 1 (ENT1) by CNX-774. We show that ENT1 mediates BQ resistance by taking up extracellular uridine, which is salvaged to generate pyrimidine nucleotides in a DHODH-independent manner. In BQ-resistant cell lines, BQ monotherapy slowed proliferation and caused modest pyrimidine nucleotide depletion, whereas combination treatment with BQ and CNX-774 led to profound cell viability loss and pyrimidine starvation. We also identify N-acetylneuraminic acid accumulation as a potential marker of the therapeutic efficacy of DHODH inhibitors. In an aggressive, immunocompetent pancreatic cancer mouse model, combined targeting of DHODH and ENT1 dramatically suppressed tumor growth and prolonged mouse survival. Overall, our study defines CNX-774 as a previously uncharacterized ENT1 inhibitor and provides strong proof of concept support for dual targeting of DHODH and ENT1 in pancreatic cancer.


Assuntos
Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Neoplasias Pancreáticas , Camundongos , Animais , Di-Hidro-Orotato Desidrogenase , Transportador Equilibrativo 1 de Nucleosídeo/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Pirimidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Nucleotídeos de Pirimidina
4.
Spectrochim Acta A Mol Biomol Spectrosc ; 284: 121798, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36054953

RESUMO

Fenamiphos (Fena), an organophosphorous pesticide, is widely used in agricultural soils to control nematodes and thrips. This nematicide is harmful to fish, birds and humans and, causes several diseases. Therefore, the determination of the nematicide is crucial. Fena has been generally detected by enzyme-based systems which require specific conditions. Herein, we integrated a xanthene moiety and a pyrimidine moiety to obtain an enzyme-free detection system for Fena and, a fluorescent sensor (N-(6-(diethylamino)-9-(pyrimidin-5-yl)-3H-xanthen-3-ylidene)-N-ethylethanaminium hexafluorophosphate(V)) (RosPm) was easily prepared. The colorimetric and spectroscopic properties of RosPm were investigated using the UV-vis and fluorescence spectroscopy. RosPm exhibited a high selectivity and sensitivity to Fena over all the metal ions, the anions and pesticides tested in acetonitrile (ACN)/water (H2O) (v:v, 1:1) solution. RosPm showed a clear visual change from purple to light-purple resulting fluorescent quenching with Fena. This sensor could be preferred for detecting Fena in vegetable samples such as tomato, pepper, and cucumber, and visualizing Fena in living MFC-7 cells.


Assuntos
Compostos Organofosforados , Praguicidas , Verduras , Acetonitrilas , Animais , Ânions , Corantes Fluorescentes/química , Humanos , Íons , Compostos Organofosforados/análise , Praguicidas/análise , Pirimidinas , Solo , Verduras/química , Poluentes Químicos da Água/análise , Xantenos
5.
J Environ Sci (China) ; 124: 76-88, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36182181

RESUMO

Mepanipyrim, an anilinopyrimidine fungicide, has been extensively used to prevent fungal diseases in fruit culture. Currently, research on mepanipyrim-induced toxicity in organisms is still very scarce, especially visual developmental toxicity. Here, zebrafish larvae were employed to investigate mepanipyrim-induced visual developmental toxicity. Intense light and monochromatic light stimuli-evoked escape experiments were used to investigate vision-guided behaviors. Meanwhile, transcriptomic sequencing and real-time quantitative PCR assays were applied to assess the potential mechanisms of mepanipyrim-induced visual developmental toxicity and vision-guided behavioral alteration. Our results showed that mepanipyrim exposure could induce retinal impairment and vision-guided behavioral alteration in larval zebrafish. In addition, the grk1b gene of the phototransduction signaling pathway was found to be a potential aryl hydrocarbon receptor (AhR)-regulated gene. Mepanipyrim-induced visual developmental toxicity was potentially related to the AhR signaling pathway. Furthermore, mepanipyrim-induced behavioral alteration was guided by the visual function, and the effects of mepanipyrim on long and middle wavelength light-sensitive opsins may be the main cause of vision-guided behavioral alteration. Our results provide insights into understanding the relationship between visual development and vision-guided behaviors induced by mepanipyrim exposure.


Assuntos
Fungicidas Industriais , Poluentes Químicos da Água , Animais , Embrião não Mamífero , Fungicidas Industriais/toxicidade , Larva , Opsinas/metabolismo , Opsinas/farmacologia , Pirimidinas , Receptores de Hidrocarboneto Arílico/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
6.
Nanotechnology ; 33(23)2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35193121

RESUMO

We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Clorofilídeos , Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Células Endoteliais/patologia , Feminino , Glutationa , Humanos , Isoquinolinas , Nanopartículas/química , Fármacos Fotossensibilizantes , Porfirinas/química , Pirazóis , Pirimidinas
7.
Mol Imaging Biol ; 24(1): 157-166, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34542805

RESUMO

PURPOSE: In this study we compared the recently developed TSPO tracer [18F]F-DPA, with [18F]DPA-714 and [11C]PBR28 by performing in vivo PET imaging on the same Alzheimer's disease mouse model APP/PS1-21 (TG) and wild-type (WT) mice with all three radiotracers. PROCEDURES: To compare the radiotracer uptake, percentage of injected dose/mL (%ID/mL), standardized uptake value ratios to cerebellum (SUVRCB), and voxel-wise analyses were performed. RESULTS: The peak uptake of [18F]F-DPA was higher than 4.3% ID/mL, while [18F]DPA-714 reached just over 3% ID/mL, and [11C]PBR28 was over 4% ID/mL in only one brain region in the WT mice. The peak/60-min uptake ratios of [18F]F-DPA were significantly higher (p < 0.001) than those of [18F]DPA-714 and [11C]PBR28. The differences in [18F]F-DPA SUVRCB between WT and TG mice were highly significant (p < 0.001) in the three studied time periods after injection. [18F]DPA-714 uptake was significantly higher in TG mice starting in the 20-40-min timeframe and increased thereafter, whereas [11C]PBR28 uptake became significant at 10-20 min (p < 0.05). The voxel-wise analysis confirmed the differences between the radiotracers. CONCLUSIONS: [18F]F-DPA displays higher brain uptake, higher TG-to-WT SUVRCB ratios, and faster clearance than [18F]DPA-714 and [11C]PBR28, and could prove useful for detecting low levels of inflammation and allow for shorter dynamic PET scans.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Animais , Encéfalo/diagnóstico por imagem , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Pirazóis , Pirimidinas
8.
Chem Pharm Bull (Tokyo) ; 70(11): 823-826, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36328525

RESUMO

Here, we synthesized three acetogenin analogs containing pyrimidine moieties linked by amine bonds, which represent the skeleton structure of pyrimidifen, a mitochondrial complex I-inhibiting insecticide. Replacing the pyrimidine moiety linked by the amine bond remarkably enhanced growth-inhibitory activity of the analogs against several human cancer cell lines. Moreover, these analogs selectively and potently inhibited the growth of these human cancer cell lines regardless of the pyrimidine substituents. Furthermore, COMPARE analyses suggested that these analogs inhibited cancer growth by inhibiting mitochondrial complex I. Our study provides insights into the design of acetogenin analogs as novel antitumor agents.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Acetogeninas , Aminas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Proliferação de Células , Estrutura Molecular
10.
Eur J Med Chem ; 244: 114875, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36332552

RESUMO

Specific inhibition on CDK9 has been proven to be a promising targeted cancer therapy. In this work, fourteen novel 2,4-disubstituted pyrimidine derivatives were designed and synthesized as potent and selective CDK9 inhibitors. These compounds showed broad anti-proliferative activities in various tumor cell lines, especially for PANC-1 cells with IC50 values as low as 0.08 µM. The most selective compound 8d was 84-fold selective for CDK9 over CDK2. Mechanism study indicated that 8d induced apoptosis of PANC-1 cells and arrested the cell cycle at G2/M phase in a dose-dependent manner. Decreased phosphorylation of the CTD of RNAPII at Ser-2 and downregulation of CDK9 were confirmed in PANC-1 cells. Besides, Molecular docking was also performed to gain insights into the ligand-binding interactions of 8d inside CDK9 and CDK2 binding sites. In vivo studies indicated that 8d exhibited potent anti-tumor effects in PANC-1 xenograft models without causing obvious loss of body weight. Our research suggests that compound 8d, as a potent CDK9 inhibitor, can be considered as a good lead-candidate for further development.


Assuntos
Antineoplásicos , Inibidores de Proteínas Quinases , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Relação Estrutura-Atividade , Pirimidinas/química , Linhagem Celular Tumoral , Apoptose , Proliferação de Células , Quinase 9 Dependente de Ciclina/metabolismo
11.
Eur J Med Chem ; 244: 114864, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36334455

RESUMO

Following our previously reported compound 3, we designed and synthesized a series of new 2-(substituted amino)- [1,2,4]triazolo[1,5-a]pyrimidines as potential tubulin polymerization inhibitors. Among them, analogue 4k, having a 3-hydroxy-4-methoxyphenylamino group, was observed to display excellent antiproliferative activity toward HeLa, HCT116, A549, and T47D with the IC50 values of 0.31, 1.28, 3.99 and 10.32 µM, respectively, which were approximately 32, 48, 4, and 5-fold improvement compared with 3. Importantly, 4k possessed significant selectivity in inhibiting cancer cell lines over the normal HEK293 cells. Moreover, futher mechanism analysis demonstrated that 4k caused G2/M arrest, induced cells apoptosis in HeLa cells, and manifested significant tubulin polymerization inhibitory activity with the IC50 value of 4.9 µM, which is comparable to CA-4 (IC50 = 4.2 µM). The observations performed in this study reveal that 2-arylamino- [1,2,4]triazolo[1,5-a]pyrimidines represent a novel class of tubulin polymerization inhibitors with potent antiproliferative efficacy.


Assuntos
Antineoplásicos , Moduladores de Tubulina , Humanos , Moduladores de Tubulina/farmacologia , Pirimidinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Apoptose , Células HeLa , Células HEK293 , Desenho de Fármacos , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Estrutura Molecular , Proliferação de Células , Pontos de Checagem da Fase G2 do Ciclo Celular , Tubulina (Proteína)/metabolismo , Polimerização
12.
Future Med Chem ; 14(22): 1649-1662, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36317642

RESUMO

Aim: Several VEGFR-2 inhibitors with the structure of [3,4-d]pyrimidine and based on sorafenib were designed and synthesized. Materials & methods: Cytotoxic activity was evaluated by MTT, wound healing and clone formation assays. Cell cycle and apoptosis were analyzed by flow cytometry. Molecular simulation and western blot were also applied. Results: Among them, II-1 significantly inhibited tumor cellular activity (IC50 = 5.90 ± 0.05 µM on HepG2 cells) compared with sorafenib (IC50 = 9.05 ± 0.54 µM on HepG2 cells). Molecular docking demonstrated that II-1 and sorafenib have the same hydrogen binding. Finally, the protein expression of phosphorylated VEGFR-2 was substantially reduced after II-1 treatment. Conclusion: Compound II-1 can inhibit VEFGR-2 activation and is an effective antitumor agent in liver cancer cells.


Assuntos
Antineoplásicos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases/química , Desenho de Fármacos , Relação Estrutura-Atividade , Sorafenibe/farmacologia , Estrutura Molecular , Relação Dose-Resposta a Droga , Proliferação de Células , Pirimidinas/química , Antineoplásicos/química
13.
Molecules ; 27(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36364312

RESUMO

Two series of cyanopyrimidine hybrids were synthesized bearing either benzo[d]imidazole, benzo[d]oxazole, benzo[d]thiazole, and benzo[b]thiophene derivatives via methylene amino linker 3a-3d (Formula A) or various sulphonamide phenyl moieties 5a-5d (Formula B) at the C-2 position. All compounds' cyclooxygenase COX-2 inhibitory activities were evaluated, and all synthesized compounds demonstrated potent activity at minimal concentrations, with IC50 values in the submicromolar range. Compounds 3b, 5b, and 5d were discovered to be the most active pyrimidine derivatives, with the highest COX-2 percent inhibition and IC50 values being nearly equal to Celecoxib and approximately 4.7-, 9.3-, and 10.5-fold higher than Nimesulide. Furthermore, the pyrimidine derivatives 3b, 5b, and 5d demonstrated anticancer activity comparable to or better than doxorubicin against four cell lines, i.e., MCF-7, A549, A498, and HepG2, with IC50 values in nanomolar in addition to low cytotoxicity on the normal W38-I cell line. The effect of compound 5d on cell cycle progression and apoptosis induction was investigated, and it was found that compound 5d could seize cell growth at the sub-G1 and G2/M phases, as well as increase the proportion of early and late apoptotic rates in MCF-7 cells by nearly 13- and 60-fold, respectively. Moreover, in silico studies for compounds 3b, 5b, and 5d revealed promising findings, such as strong GIT absorption, absence of BBB permeability, nil-to-low drug-drug interactions, good oral bioavailability, and optimal physicochemical properties, indicating their potential as promising therapeutic candidates.


Assuntos
Antineoplásicos , Inibidores de Ciclo-Oxigenase 2 , Humanos , Simulação de Acoplamento Molecular , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Pirimidinas/farmacologia , Pirimidinas/química , Estrutura Molecular , Desenho de Fármacos
14.
Ther Adv Respir Dis ; 16: 17534666221135322, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36346055

RESUMO

Dasatinib, a tyrosine kinase inhibitor, is usually prescribed for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, some patients may develop an intolerance to this drug over the years. Among various toxicities related to dasatinib, dasatinib-associated interstitial pneumonitis is not reported frequently in the literature yet. Moreover, published studies have reported only few cases of dasatinib-associated pneumonitis, almost exclusively in chronic myeloid leukemia. In this study, we describe three cases of dasatinib-associated interstitial pneumonitis in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (a 56-year-old man, a 34-year-old man, and a 46-year-old woman) at our institution. In all three patients, the time from the initiation of dasatinib therapy to the onset of interstitial pneumonitis varied greatly. Among them, one patient underwent a surgical lung biopsy, which revealed chronic granulomatous inflammation without any causative pathogen. In all patients, dasatinib was discontinued after the diagnosis of interstitial pneumonitis, and two patients were treated with systemic steroids. Although infrequent, dasatinib-induced pneumonitis should be considered a possible diagnosis in dasatinib-treated patients with fever and respiratory symptoms. In addition, hematologists and pulmonologists should be aware of this rare but critical toxicity.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Doenças Pulmonares Intersticiais , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Adulto , Dasatinibe/efeitos adversos , Cromossomo Filadélfia , Pirimidinas/efeitos adversos , Tiazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Inibidores de Proteínas Quinases/uso terapêutico , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnóstico
15.
Sci Rep ; 12(1): 19067, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352054

RESUMO

The effect of moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of the dual endothelin receptor antagonist aprocitentan was clinically investigated as 25% of aprocitentan is cleared through the liver. Aprocitentan is in clinical development for the treatment of resistant hypertension. This was an open-label, Phase 1 study. Subjects were recruited in two groups (i.e., moderate hepatic impairment (Child-Pugh B; n = 8) and matched healthy subjects (n = 9) and received a single oral dose of 25 mg aprocitentan. Thereafter, they were observed for 14 days. Due to personal reasons one healthy subject discontinued the study. The PK of aprocitentan were similar between subjects with moderate hepatic impairment and healthy subjects, with maximum plasma concentrations (Cmax) reached at 4.0 h. There was no difference in Cmax, indicated by the geometric means ratio (90% confidence interval) of 1.03 (0.86-1.24). There was a lower apparent clearance, a similar apparent volume of distribution, a longer terminal half-life (56.4 h vs 48.3 h in healthy subjects), and an increase in area under the curve from zero to infinity of 23% in moderate hepatically impaired subjects compared to healthy subjects. There were no differences observed in plasma protein binding (range 98.7-99.0%). Aprocitentan was well tolerated, and headache was the only adverse event reported by one subject. In conclusion, there were no clinically relevant differences in PK between subjects with moderate hepatic impairment and healthy subjects. Based on these results, aprocitentan can be administered in subjects with mild and moderate hepatic impairment and dose adjustment is not required.Clinical Trial Registration ClinicalTrials.gov NCT04252495.


Assuntos
Antagonistas dos Receptores de Endotelina , Hepatopatias , Humanos , Área Sob a Curva , Antagonistas dos Receptores de Endotelina/efeitos adversos , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Pirimidinas , Sulfonamidas
17.
J Hematol Oncol ; 15(1): 166, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36380319

RESUMO

Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and clinical efficacy. Nemtabrutinib is a next generation, reversible inhibitor of BTK that potently inhibits BCR signaling in treatment-naïve and ibrutinib-refractory CLL cells ex vivo. The clinical efficacy of combining BTK inhibitors with BCL2 inhibitors motivated us to evaluate the novel combination of nemtabrutinib and venetoclax. In vitro studies show that nemtabrutinib and venetoclax are not antagonistic to each other. In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.


Assuntos
Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Linfoma de Células B , Camundongos , Animais , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Tirosina Quinase da Agamaglobulinemia , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2 , Inibidores de Proteínas Quinases/uso terapêutico
18.
Molecules ; 27(22)2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36432130

RESUMO

A series of novel 4-(aryl)-benzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles were obtained through the Povarov (aza-Diels-Alder) and oxidation reactions, starting from benzimidazole-2-arylimines. Based on the literature data and X-ray diffraction analysis, it was discovered that during the Povarov reaction, [1,3] sigmatropic rearrangement leading to dihydrobenzimidazo[1,2-a]pyrimidines took place. The structures of all the obtained compounds were confirmed based on the data from 1H- and 13C-NMR spectroscopy, IR spectroscopy, and elemental analysis. For all the obtained compounds, their photophysical properties were studied. In all the cases, a positive emission solvatochromism with Stokes shifts from 120 to 180 nm was recorded. Aggregation-Induced Emission (AIE) has been illustrated for compound 6c using different water fractions (fw) in THF. The compounds 6c and 6f demonstrated changes in emission maxima or/and intensities after mechanical stimulation.


Assuntos
Corantes Fluorescentes , Pirimidinas , Teoria da Densidade Funcional , Pirimidinas/química , Corantes Fluorescentes/química , Ionóforos , Espectroscopia de Ressonância Magnética
19.
Molecules ; 27(22)2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36432205

RESUMO

A series of novel pinanyl pyrimidine amine derivatives (1e~1n) and camphoryl pyrimidine amine derivatives (2b~2f) bearing bicyclic monoterpene moieties were designed and synthesized from natural and renewable nopinone and camphor. All chemical structures of target compounds were characterized by 1H NMR, 13C NMR and HRMS spectra analyses, and the antimicrobial activities were evaluated. The results indicated that most compounds showed considerable antibacterial and antifungal activities against Klebsiella pneumoniae, Streptococcus pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Methicillin-Resistant Staphylococcus aureus (MRSA), Bacillus cereus and Candida albicans. Among them, 1f showed potent antibacterial activity against all tested bacteria, 1i exhibited excellent inhibition against Streptococcus pneumoniae (1 µg/mL) and Escherichia coli (1 µg/mL), which was better than the control drug amikacin (2 µg/mL). As to antifungal activity against Candida albicans (C. albicans), compound 1l showed comparable activity (16 µg/mL) to the control drug ketoconazole. Furthermore, five active compounds with better antimicrobial activities also showed anti-inflammatory potencies against mouse mononuclear macrophages leukemia cells (RAW). Especially, 1f (IC50 = 1.37 µM) and 2f (IC50 = 1.87µM) are more potent than the control drug aspirin (IC50 = 1.91 µM).


Assuntos
Antifúngicos , Staphylococcus aureus Resistente à Meticilina , Camundongos , Animais , Testes de Sensibilidade Microbiana , Antifúngicos/química , Monoterpenos/farmacologia , Aminas , Pirimidinas , Antibacterianos/química , Candida albicans , Escherichia coli , Monoterpenos Bicíclicos
20.
Cells ; 11(22)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36429097

RESUMO

Finding synergistic drug combinations is an important area of cancer research. Here, we sought to rationally design synergistic drug combinations with an inhibitor of BTK kinase, ibrutinib, which is used for the treatment of several types of leukemia. We (a) used a pooled shRNA screen to identify genes that protect cells from the drug, (b) identified protective pathways via bioinformatics analysis of these gene sets, and (c) identified drugs that inhibit these pathways. Based on this analysis, we established that inhibitors of proteasome and mTORC1 could synergize with ibrutinib both in vitro and in vivo. We suggest that FDA-approved inhibitors of these pathways could be effectively combined with ibrutinib for the treatment of chronic lymphocytic leukemia (CLL).


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Combinação de Medicamentos , RNA Interferente Pequeno/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...