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1.
Molecules ; 27(3)2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35164014

RESUMO

Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC50 values of 7.2, 6.4, and 7.3 µM, respectively, and were all more potent than imatinib (IC50 of 65.4 µM). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 µM, showed an IC50 value of 35.8 µM (imatinib, IC50 = 0.08 µM). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer.


Assuntos
Proliferação de Células/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Neoplasias/patologia , Células A549 , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/uso terapêutico , Células K562 , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
2.
Biomed Chromatogr ; 35(7): e5088, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33590534

RESUMO

A salting-out-assisted switchable hydrophilicity solvent-based liquid phase microextraction (SA-SHS-LPME) was developed for the separation and determination of trace amounts of imatinib and N-desmethyl imatinib in biological and environmental samples by HPLC-UV. Triethylamine as a hydrophobic compound and protonated triethylamine carbonate as a hydrophilic one were switched by the addition or elimination of CO2 . The use of NaOH resulted in the elimination of CO2 from the sample solution, which led to the conversion of P-TEA-C into triethylamine (TEA) and as a result, the analytes was extracted and entered the TEA phase. The salting out was performed to speed up the formation of the TEA in the shape of fine droplets in the specimen solution. Furthermore, the impact of several momentous factors that influence the recovery of the extraction was investigated. Under the optimum conditions, the limit of detection and limit of quantification were obtained in ranges of 0.03-0.05 and 0.1-0.15 µg L-1 for imatinib and 0.04-0.06 and 0.13-0.20 µg L-1 for N-desmethyl imatinib, respectively. The preconcentration factor was 250. Inter- and intraday precision (RSD, n = 5) was <5%. In the case of imatinib and N-desmethyl imatinib in biological and environmental specimens, a range of 97.0-102% was obtained as the recovery.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Mesilato de Imatinib , Microextração em Fase Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/análise , Mesilato de Imatinib/isolamento & purificação , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Cloreto de Sódio/química , Solventes/química
3.
J Med Chem ; 62(6): 3122-3134, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30873837

RESUMO

Imatinib mesylate, 1a, inhibits production of ß-amyloid (Aß) peptides both in cells and in animal models. It reduces both the ß-secretase and γ-secretase cleavages of the amyloid precursor protein (APP) and mediates a synergistic effect, when combined with a ß-secretase inhibitor, BACE IV. Toward developing more potent brain-permeable leads, we have synthesized and evaluated over 75 1a-analogues. Several compounds, including 2a-b and 3a-c, inhibited production of Aß peptides with improved activity in cells. These compounds affected ß-secretase cleavage of APP similarly to 1a. Compound 2a significantly reduced production of the Aß42 peptide, when administered (100 mg/kg, twice daily by oral gavage) to 5 months old female mice for 5 days. A combination of compound 2a with BACE IV also reduced Aß levels in cells, more than the additive effect of the two compounds. These results open a new avenue for developing treatments for Alzheimer's disease using 1a-analogues.


Assuntos
Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/química , Antineoplásicos/farmacologia , Mesilato de Imatinib/análogos & derivados , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular , Desenvolvimento de Medicamentos , Feminino , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Camundongos Transgênicos , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 158: 937-950, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30261468

RESUMO

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme and a survival-enhancing factor in a number of cancers. Chronic myeloid leukemia (CML) is a blood cancer caused by pathological kinase activity of the BCR-ABL protein, currently treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM). However, resistance to TKIs persists in a number of patients and HO-1 overexpression has been linked with the induction of chemoresistance in CML. With this in mind, in this study, we designed and synthesized the first series of hybrid compounds obtained by combining the structures of IM, as BCR-ABL inhibitor, with imidazole-based HO-1 inhibitors. We found that many hybrids were able to inhibit the enzymatic activity of both targets and to reduce the viability of CML-IM resistant cells, showing that a single molecular entity may reduce the resistance phenomenon.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Antineoplásicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Mesilato de Imatinib/síntese química , Imidazóis/síntese química , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Simulação de Acoplamento Molecular
5.
Future Med Chem ; 10(12): 1421-1433, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29788766

RESUMO

AIM: Imatinib possesses various mechanisms for combating cancer, making the development of imatinib analogs an attractive target for cancer research. METHOD: Two series of analogs were designed and synthesized, maintaining the essential pharmacophoric features in imatinib structure. The synthesized compounds were subjected to cell-based antiproliferative assays against nonsmall lung (A549) and colon cancer cell lines. In addition, flow cytometry cell cycle and caspase-3 colorimetric assays were performed. RESULTS: Most compounds showed potent anticancer activity against both cell lines with IC50 = 0.14-5.07 µM. Three compounds demonstrated ability to reinforce cell cycle arrest at G1 stage in a manner similar to imatinib. In addition, they induced apoptosis via activation of caspase-3.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/farmacologia , Células A549 , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mesilato de Imatinib/síntese química , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Relação Quantitativa Estrutura-Atividade
6.
Sci Rep ; 8(1): 6846, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29717168

RESUMO

The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.


Assuntos
Mesilato de Imatinib/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Regulação Alostérica , Ácidos e Sais Biliares/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/química , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/química , Fatores de Transcrição/análise , Fatores de Transcrição/metabolismo
7.
Biomed Chromatogr ; 31(12)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28621487

RESUMO

The aim of this study was to improve and validate a more stable and less time-consuming method based on liquid chromatography and tandem mass spectrometry (LC- MS/MS) for the quantitative measurement of imatinib and its metabolite N-demethyl-imatinib (NDI) in human plasma. Separation of analytes was performed on a Waters XTerra RP18 column (50 × 2.1 mm i.d., 3.5 µm) with a mobile phase consisting of methanol-acetonitrile-water (65:20:15, v/v/v) with 0.05% formic acid at a flow-rate of 0.2 mL/min. The Quattro MicroTM triple quadruple mass spectrometer was operated in the multiple-reaction-monitoring mode via positive electrospray ionization interface using the transitions m/z 494.0 → 394.0 for imatinib, m/z 479.6 → 394.0 for NDI and m/z 488.2 → 394.0 for IS. The method was linear over 0.01-10 µg/mL for imatinib and NDI. The intra- and inter-day precisions were all <15% in terms of relative standard deviation, and the accuracy was within ±15% in terms of relative error for both imatinib and NDI. The lower limit of quantification was identifiable and reproducible at 10 ng/mL. The method was sensitive, specific and less time-consuming and it was successfully applied in gastrointestinal stromal tumor patients treated with imatinib.


Assuntos
Antineoplásicos , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib , Adulto , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Feminino , Humanos , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/sangue , Mesilato de Imatinib/uso terapêutico , Limite de Detecção , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
8.
Angew Chem Int Ed Engl ; 55(38): 11629-32, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27511868

RESUMO

The palladium-catalyzed defluorinative coupling of 1-aryl-2,2-difluoroalkenes with boronic acids is described. Broad functional-group tolerance arises from a redox-neutral process by a palladium(II) active species which is proposed to undergo a ß-fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (≥50:1) in all cases, and it is critical, as traditional chromatographic techniques often fail to separate monofluoroalkene isomers. As a demonstration of this method's unique combination of reactivity and functional-group tolerance, a Gleevec® analogue, using a monofluorostilbene as an amide isostere, was synthesized.


Assuntos
Alcenos/química , Ácidos Borônicos/química , Paládio/química , Estilbenos/química , Catálise , Flúor/química , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/síntese química , Estereoisomerismo , Estilbenos/síntese química
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 24(3): 755-9, 2016 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-27342504

RESUMO

OBJECTIVE: To investigate the growth inhibitory effect of Imatinib derivative TEB-415 on various multiple myeloma (MM) cell lines, such as U226, H929, RPMI8226, MM1R and MM1S. METHODS: TEB-415, a derivative of Imatinib was synthesized by modifying the chemical structure of Imatinib. MM cell lines (U226, H929, RPMI8226, MM1R and MM1S) were treated with TEB-415, Imatini and Bortezomib of various concentrations. Cells were grown for 72 hours and the growth rate was measured by CCK-8 method, cell morphology was observed and the IC50 was calculated. RESULTS: TEB-415 could inhibit H929 and RPMI8226 growth significantly. When the concentration of TEB-415 was <0.1 nmol/L, >50% H929 cells died. The IC50 of Imatinib was 0.123 mol/L while the IC50 of Bortezomib was 0.03 nmol/L. In RPMI8226 cell line, when the concentration of TEB-415 was 11.9 mol/L, more than 50% of cells died. In contrast, when RPMI8266 were treated with Imatinib of the concentration of 12.8 mol/L, cells grew normally. CONCLUSION: In comparison to Imatinib, TEB-415, a derivative of Imatinib, can kill H929 MM cells much effectively, its effecacy is only inferior to Bortezomib. RPMI8226, an MM cell line is insensitive to Imatinib, but still sensitive to TEB-415 and its growth can be inhibited by TEB-415.


Assuntos
Mesilato de Imatinib/farmacologia , Mieloma Múltiplo/patologia , Apoptose , Bortezomib , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Mesilato de Imatinib/análogos & derivados
10.
Bioorg Med Chem Lett ; 26(5): 1419-27, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26850004

RESUMO

Three novel series of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib were prepared and evaluated in vitro for their cytostatic effects against a human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and human leukemia stem-like cell line (KG1a). The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analog. Benzene and piperazine rings were necessary groups in these compounds for maintaining inhibitory activities against the K562 and HL60 cell lines. Introducing a trifluoromethyl group significantly enhanced the potency of the compounds against these two cell lines. Surprisingly, some compounds showed significant inhibitory activities against KG1a cells without inhibiting common leukemia cell lines (K562 and HL60). These findings suggest that these compounds are able to inhibit leukemia stem-like cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/farmacologia , Oxidiazóis/farmacologia , Triazóis/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Mesilato de Imatinib/síntese química , Mesilato de Imatinib/química , Células K562 , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
11.
ChemMedChem ; 11(1): 31-7, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26585829

RESUMO

A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/síntese química , Mesilato de Imatinib/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade
12.
Expert Opin Ther Pat ; 25(12): 1411-21, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26372795

RESUMO

INTRODUCTION: The Bcr-Abl inhibitor imatinib was approved in 2001 for chronic myeloid leukemia therapy, and dramatically changed the lives of patients affected by this disease. Since it also inhibits platelet derived growth factor receptor (PDGFR) and c-Kit, imatinib is used for various other tumors caused by abnormalities of one or both these two enzymes. AREAS COVERED: This review presents an overview on imatinib formulations and derivatives, synthetic methodologies and therapeutic uses that have appeared in the patent literature since 2008. EXPERT OPINION: Innovative imatinib formulations, such as nanoparticles containing the drug, will improve its bioavailability. Moreover, oral solutions or high imatinib content tablets or capsules will improve patient compliance. Some solid formulations and innovative syntheses that have appeared in the last few years will reduce the cost of the drug, offering big advantages for poor countries. Some recently patented efficacious imatinib derivatives are in preclinical studies and could enter clinical trials in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.


Assuntos
Antineoplásicos/administração & dosagem , Desenho de Fármacos , Mesilato de Imatinib/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Química Farmacêutica/métodos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/farmacologia , Nanopartículas , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Patentes como Assunto
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