Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 697
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Med Chem ; 186: 111888, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31787359

RESUMO

Targeting L858R/T790M/C797S mutant EGFR is a major challenge in the new-generation EGFR tyrosine kinase inhibitors development for conquering drug resistant NSCLC. In this study, a series of novel 9-heterocyclyl substituted 9H-purine derivatives were designed as EGFRL858 R/T790 M/C797S tyrosine kinase inhibitors. Among these compounds, D4, D9, D11 and D12 showed significantly potent anti-proliferation and EGFRL858 R/T790 M/C797S inhibition activity. In particular, the most potent compound D9 showed anti-proliferation against HCC827 and H1975 cell lines with the IC50 values of 0.00088 and 0.20 µM, respectively. And D9 inhibited the EGFRL858R/T790M/C797S with an IC50 value of 18 nM. Furtherly, D9 could significantly suppress the EGFR phosphorylation, induce the apoptosis, arrest cell cycle at G0/G1, and inhibit colony formation in HCC827 cell line by a concentration-dependent manner. Molecular docking indicated that the introduction of a cyclopropylsulfonamide group in D9 led to the formation of additional two hydrogen bonds with mutant Ser797 which played key roles in generating efficient EGFRL858 R/T790 M/C797S inhibitory activity. These findings strongly indicated that 9-heterocyclyl substituted 9H-purine derivatives were promising L858R/T790M/C797S mutant EGFR-TKIs. The introduction of extra hydrogen bond interaction with mutant Ser797 is efficient method for the design of the fourth-generation EGFR-TKIs.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Purinas/síntese química , Purinas/química , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 184: 111728, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610375

RESUMO

A new series of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives were designed, synthesized and demonstrated to act as tubulin polymerization inhibitors. These new derivatives showed significant antitumor activities, among which SKLB0533 demonstrated to be the most potent compound, with IC50 values ranging from 44.5 to 135.5 nM against seven colorectal carcinoma (CRC) cell lines. Remarkably, SKLB0533 exhibited no activity against other potential targets, such as 420 kinases and EZH2. Besides, SKLB0533 inhibited tubulin polymerization, arrested the cell cycle at the G2/M phase and induced apoptosis in CRC cells. Furthermore, SKLB0533 suppressed tumour growth in the HCT116 xenograft model without inducing notable major organ-related toxicity, suggesting that SKLB0533 could be used as a promising lead compound for the development of new antitumor agents.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Purinas/farmacologia , Piridonas/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Purinas/síntese química , Purinas/química , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Eur J Med Chem ; 182: 111663, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31514019

RESUMO

Receptor tyrosine kinase PDGFRα is often constitutively activated in various tumours and is regarded as a drug target. Here, we present a collection of 2,6,9-trisubstituted purines with nanomolar potency against PDGFRα and strong and selective cytotoxicity in the human eosinophilic leukaemia cell line EOL-1 that expresses the FIP1L1-PDGFRA oncogene. In treated EOL-1 cells, the example compound 14q inhibited the autophosphorylation of PDGFRα and the phosphorylation of STAT3 and ERK1/2. Interestingly, we observed pronounced and even increased effects of 14q on PDGFRα and some of its downstream signalling pathways after drug washout. In accordance with suppressed PDGFRα signalling, treated cells were arrested in the G1 phase of the cell cycle and eventually underwent apoptosis. Our results show that substituted purines can be used as specific modulators of eosinophilic leukaemia.


Assuntos
Antineoplásicos/farmacologia , Síndrome Hipereosinofílica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Síndrome Hipereosinofílica/metabolismo , Síndrome Hipereosinofílica/patologia , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Purinas/síntese química , Purinas/química , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Chem Commun (Camb) ; 55(74): 11147-11150, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31464306

RESUMO

Photocaging of a tight-binding bisubstrate inhibitor of cAMP-dependent protein kinase (PKA) with a nitrodibenzofuran-based group fully abolished its inhibitory potency. The affinity difference between the photocaged and the active inhibitor was over 5 orders of magnitude. The photocaged inhibitor disrupted the PKA holoenzyme in cell lysates upon photolysis under a 398 nm LED.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dibenzofuranos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Animais , Células CHO , Cricetulus , Dibenzofuranos/síntese química , Dibenzofuranos/química , Dibenzofuranos/efeitos da radiação , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/efeitos da radiação , Purinas/síntese química , Purinas/química , Purinas/efeitos da radiação , Raios Ultravioleta
5.
Eur J Med Chem ; 179: 218-232, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254923

RESUMO

Sustained activation of STAT3 is closely related to the cancer development, but the inhibitors for STAT3 overexpression are still in the clinical research stage. In this study, a series of 2,6-disubstituted purine derivatives were designed and synthesized, and their biological activities, as small molecule inhibitors of STAT3, were assessed. Compound PD26-TL07 exhibited remarkable antiproliferative activity against three cancer cell lines (IC50 values for HCT-116, SW480 and MDA-MB-231 were 1.77 ±â€¯0.35, 1.51 ±â€¯0.19, and 1.25 ±â€¯0.38 µM, respectively). Moreover, detailed biological assays revealed that PD26-TL07 could effectively inhibited STAT3 phosphorylation, and had little inhibition to others'. The newly discovered PD26-TL07 displayed an expecting anticancer effect both in vitro and in vivo. The molecular docking models revealed that PD26-TL07 could bind to the SH2 domain of STAT3. Three additional compounds (PD26-BZ01, PD26-TL03 and PD26-AS06) were also able to inhibit this phosphorylation. This study described novel 2,6-disubstituted purine derivatives as potent anticancer agents targeting STAT3.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Purinas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Purinas/síntese química , Purinas/química , Fator de Transcrição STAT3/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 176: 393-409, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125894

RESUMO

Novel substituted purine isosters, were designed and synthesized as potential inhibitors of the Epidermal Growth Factor Receptor (EGFR). The compounds were rationally designed through bioisosteric replacement of the central quinazoline core of lapatinib, an approved drug that inhibits both EGFR and HER2, another important member of this family of receptors. The new target molecules were evaluated as inhibitors of receptor phosphorylation at the cellular level, for their direct inhibitory action on the intracellular receptor kinase domain and for their cytotoxicity against the non-small cell lung cancer cell line A549 and breast cancer HCC1954, cell lines which are associated with overexpression of EGFR and HER2, respectively. The most potent derivatives were further studied for their cellular uptake levels and in vivo pharmacokinetic properties. One compound (23) displayed a noteworthy pharmacokinetic profile, and higher intracellular accumulation in comparison to lapatinib in the A549 cells, possibly due to its higher lipophilicity. This lead compound (23) was assessed for its efficacy in an EGFR positive xenograft model, where it successfully inhibited tumor growth, with a similar efficacy with that of lapatinib and with minimal phenotypic toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Lapatinib/análogos & derivados , Lapatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Domínio Catalítico , Linhagem Celular Tumoral , Feminino , Humanos , Lapatinib/síntese química , Lapatinib/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Purinas/síntese química , Purinas/química , Purinas/farmacocinética , Receptor ErbB-2/química
8.
Curr Protoc Nucleic Acid Chem ; 77(1): e78, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30912630

RESUMO

Nucleic acid triplexes are formed when a DNA or RNA oligonucleotide binds to a polypurine-polypyrimidine-rich sequence. Triplexes have wide therapeutic applications such as gene silencing or site-specific mutagenesis. In addition, protocols based on triplex-affinity capture have been used for detecting nucleic acids in biosensing platforms. In this article, the design, synthesis, and use of parallel clamps and polypurine-reversed hairpins (PPRH) to bind to target polypyrimidine targets are described. The combination of the polypurine Watson-Crick strand with the triplex-forming strand in a single molecule produces highly stable triplexes allowing targeting of single- and double-stranded nucleic acid sequences. On the other hand, PPRHs are easily prepared and work at nanomolar range, like siRNAs, and at a lower concentration than that needed for antisense ODNs or TFOs. However, the stability of PPRHs is higher than that of siRNAs. In addition, PPRHs circumvent off-target effects and are non-immunogenic. © 2019 by John Wiley & Sons, Inc.


Assuntos
Inativação Gênica , Purinas/química , Técnicas Biossensoriais , Ouro/química , Purinas/síntese química , Análise de Sequência , Software , Ressonância de Plasmônio de Superfície , Propriedades de Superfície
9.
Eur J Med Chem ; 168: 28-44, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30798051

RESUMO

The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200 µM and among them three derivatives (12, 13 and 18) exhibited Ki in the sub-millimolar range (0.84, 2.4 and 0.58 mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter.


Assuntos
5'-Nucleotidase/antagonistas & inibidores , Antineoplásicos/farmacologia , Purinas/farmacologia , 5'-Nucleotidase/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Modelos Moleculares , Estrutura Molecular , Purinas/síntese química , Purinas/química , Relação Estrutura-Atividade
10.
Future Med Chem ; 11(2): 83-95, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30644318

RESUMO

AIM: Identification of new antiproliferative compounds. METHODOLOGY: Four series of compounds were synthesized by the Mitsunobu reaction. Their antiproliferative activity was studied against several cancer cells and a noncancerous fibroblast cell line. Their apoptotic activity was analyzed using a caspase 3/7 fluorescence assay. RESULTS & CONCLUSION: 9-alkylated-6-halogenated and 2,6-dihalogenated purines show remarkable inhibition of tumor cell proliferation, with the dichloro derivatives being the most potent of all the series. The most promising compound, tetrahydroquinoline 4c, exhibits significant antiproliferative activity against the cancer cells tested, while displaying a 19-fold lower potency against noncancerous fibroblasts, a key feature that indicates potential selectivity against cancer cells. This compound produces a high percentage of apoptosis (58%) after 24 h treatment in human breast cancer MCF-7 cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Purinas/química , Purinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HCT116 , Halogenação , Humanos , Células MCF-7 , Purinas/síntese química , Quinolinas/síntese química , Relação Estrutura-Atividade
11.
Molecules ; 24(2)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669410

RESUMO

The biology of the group of plant hormones termed cytokinins is reviewed to reveal areas where further studies of cytokinin-binding proteins could be significant. Such areas include: inhibition of human tumour cell growth by cytokinin ribosides, the role of cytokinins in the development of diverse micro-organisms including the cyanobacteria and Mycobacterium tuberculosis, the very rapid responses of plant cells to exogenous cytokinins, and other aspects of cytokinin plant biology. Photoaffinity labelling (PAL) coupled to the recent advances in HPLC of proteins and mass spectral analysis and sequencing of proteins, may have relevance to these areas. To facilitate PAL, we present experimental details for two methods for synthesis of 8-azido-N6-benzyladenine, which has the azido affinity group in the preferred position of the purine ring. Synthesis from [2-³H]adenosine yielded the above-mentioned PAL reagent with ³H in the purine ring and also gave labelled 9-riboside and 8-azido-N6,9-dibenzyladenine. 8-Azido-N6-benzyladenine was also prepared from 6,8-dichloropurine by a facile synthesis, which would allow a label to be sited in the benzyl group where substituents can also be introduced to vary cytokinin activity. The use of inactive cytokinin analogues in assessing the significance of PAL is discussed.


Assuntos
Compostos de Benzil/síntese química , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Técnicas de Química Sintética , Citocininas/metabolismo , Processos Fotoquímicos , Purinas/síntese química , Adenosina/análogos & derivados , Adenosina/química , Compostos de Benzil/química , Cloroquinolinóis/química , Estrutura Molecular , Purinas/química , Coloração e Rotulagem
12.
J Labelled Comp Radiopharm ; 62(2): 62-66, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30375008

RESUMO

Starting from N,N-dimethylamine and D2 O, deuterated fragment of ribociclib was synthesized for use as a mass spectroscopy internal standard. Furthermore, systematic studies on D0 (unlabeled material) formation during the amidation reaction were performed, leading to the identification of a coupling reagent, HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), as main cause. Finally, an alternative route was designed using EDCI/HOBT as coupling reagents to produce the desired deuterated compound without D0 residue.


Assuntos
Aminopiridinas/síntese química , Deutério/química , Purinas/síntese química , Espectrometria de Massas/normas , Compostos de Piridínio/química , Triazóis/química
13.
Cent Nerv Syst Agents Med Chem ; 19(1): 31-45, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30465516

RESUMO

BACKGROUND: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. METHODS: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1 . RESULTS AND CONCLUSION: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.


Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacocinética , Desenho de Drogas , Purinas/síntese química , Purinas/farmacocinética , Animais , Anticonvulsivantes/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Masculino , Camundongos , Purinas/uso terapêutico , Relação Quantitativa Estrutura-Atividade , Convulsões/tratamento farmacológico , Convulsões/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-30526265

RESUMO

Syntheses of α-branched alkyl and aryl substituted 9-[2-(phosphonomethoxy)ethyl]purines from substituted 1,3-dioxolanes have been developed. Key synthetic precursors, α-substituted dialkyl [(2-hydroxyethoxy)methyl]phosphonates were prepared via Lewis acid mediated cleavage of 1,3-dioxolanes followed by reaction with dialkyl or trialkyl phosphites. The best preparative yields were achieved under conditions utilizing tin tetrachloride as Lewis acid and triisopropyl phosphite. Attachment of purine bases to dialkyl [(2-hydroxyethoxy)methyl]phosphonates was performed by Mitsunobu reaction. Final α-branched 9-[2-(phosphonomethoxy)ethyl]purines were tested for antiviral, cytostatic and antiparasitic activity, the latter one determined as inhibitory activity towards Plasmodium falciparum enzyme hypoxanthine-guanine-xanthine phosphoribosyltransfesase. In most cases biological activity was only marginal.


Assuntos
Antiparasitários/farmacologia , Antivirais/farmacologia , Vírus de DNA/efeitos dos fármacos , Dioxolanos/química , Inibidores Enzimáticos/farmacologia , Pentosiltransferases/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Purinas/farmacologia , Animais , Antiparasitários/síntese química , Antiparasitários/química , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pentosiltransferases/metabolismo , Plasmodium falciparum/enzimologia , Purinas/síntese química , Purinas/química
15.
Molecules ; 23(8)2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30103421

RESUMO

Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1⁻3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1⁻3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Purinas/síntese química , Purinas/farmacologia , Antineoplásicos/química , Neoplasias da Mama , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Neoplasias Colorretais , Feminino , Humanos , Masculino , Micro-Ondas , Estrutura Molecular , Purinas/química , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 155: 406-417, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29906687

RESUMO

Based on the potent anticancer activity of 6'-fluorocyclopentenyl-cytosine 2b in phase IIa clinical trials for the treatment of gemcitabine-resistant pancreatic cancer, we carried out a systematic structure-activity relationship study of 6'-fluorocyclopentenyl-pyrimidines 3a-i and -purines 3j-o to discover novel anticancer agents. We also synthesized the phosphoramidate prodrug 3p of adenine derivative 1b to determine if the anticancer activity depended on the inhibition of DNA and/or RNA polymerase in cancer cells and/or on the inhibition of S-adenosylhomocysteine (SAH) hydrolase. All of the synthesized pyrimidine nucleosides exhibited much less potent anticancer activity in vitro than the cytosine derivative 2b, acting as RNA and/or DNA polymerase inhibitor, indicating that they could not be efficiently converted to their triphosphates for anticancer activity. Among all the synthesized purine nucleosides, adenine derivative 1b and N6-methyladenine derivative 3k showed potent anticancer activity, showing equipotent inhibitory activity as the positive control, neplanocin A (1a) or Ara-C. However, the phosphoramidate prodrug 3p showed less anticancer activity than 1b, indicating that it did not act as a RNA and/or DNA polymerase inhibitor like 2b. This result also demonstrates that the anticancer activity of 1b largely depends on the inhibition of histone methyltransferase, resulting from strong inhibition of SAH hydrolase. The deamination of the N6-amino group, the addition of the bulky alkyl group at the N6-amino group, or the introduction of the amino group at the C2 position almost abolished the anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Ciclopentanos/farmacologia , Desenho de Drogas , Hidrocarbonetos Fluorados/farmacologia , Pró-Fármacos/farmacologia , Purinas/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/síntese química , Ciclopentanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Purinas/síntese química , Purinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
17.
Future Med Chem ; 10(12): 1449-1464, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29788781

RESUMO

AIM: Targeting apoptosis regulators such as caspases aiming at inducing apoptosis is an attractive strategy in cancer therapy. MATERIALS & METHODS: 8-substituted purine incorporating pyrazole moiety were designed, synthesized and evaluated for their anticancer and antioxidant activities. RESULTS: Compounds 7a and 8a displayed potent and selective anticancer activity against lung cancer A549 cell line with low cytotoxicity on peripheral blood mononuclear normal cells. Compounds 7a and 8a induced caspase dependent apoptotic death and DNA damage in all cancer cell lines. In addition, compounds 2, 5, 6a, 7a, 8a, 8c, 11a, 11b and 12b showed good antioxidant activity higher than that of the standard ascorbic acid. CONCLUSION: Compounds 7a and 8a can be considered promising dual anticancer and antioxidant leads inducing caspase-dependent apoptotic death and DNA damage.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Purinas/química , Purinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Células A549 , Antineoplásicos/síntese química , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Purinas/síntese química , Relação Estrutura-Atividade , Triazóis/síntese química
18.
Eur J Med Chem ; 151: 836-848, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29684894

RESUMO

Checkpoint kinase 1 (CHK1) inhibitors can potentiate the effectiveness of deoxyribonucleic acid (DNA) damaging agents in the treatment of cancer. A novel series of 2,6-disubstituted-9H-purine (3a-p, 5a and 5b), 2,4-disubstituted-thieno[3,2-d]pyrimidine (8a-c) and 2,4-disbustituted-7H-pyrrolo[2,3-d]pyrimidine (11a-c) analogues were designed and synthesized as potent CHK1 inhibitors. Compounds (3a, 3d, 3f and 3j-l) with 9H-purine core displayed more potent inhibition against CHK1. The most potent compound (3l) also exhibited low anti-proliferative effects towards HT29 and Hek293 cell lines. In addition, 3l showed strong potentiating effect (7-fold) on the anti-proliferative activity of gemcitabine towards HT29 cells. The results of cell cycle assay indicated that 3l could strikingly affect the cell cycle distribution of the gemcitabine-treated HT29 cells and induce a significant S phase accumulation. The kinase selectivity profile of 3l displayed acceptable selectivity against other kinases. These results rendered 3l a potent lead compound of CHK1 inhibitor for further investigation.


Assuntos
Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Purinas/química , Purinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Células HT29 , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Purinas/síntese química , Pirimidinas/síntese química , Relação Estrutura-Atividade
19.
Bioorg Med Chem ; 26(8): 1810-1822, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29486953

RESUMO

Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.


Assuntos
Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/genética , Receptores ErbB/metabolismo , Células HT29 , Humanos , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Purinas/síntese química , Purinas/química , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 149: 10-21, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29494841

RESUMO

In order to study the anti-inflammatory activity of novel 6-substituted and 6,9-disubstituted purine derivatives, 20 compounds, L1-10 and W1-10, derived from purine and lacking a gold complex were designed, synthesized and their anti-inflammatory activity was screened. LPS-induced TNF-α, IL-1ß, IL-6, PGE2, NO, COX-2 and iNOS mRNA were evaluated, and western blot and NF-κB p65 translocation assay were performed in RAW 264.7 macrophages. Furthermore, carrageenan-induced hind paw edema experiments were performed in mice. Compound L1, L4, W2, and W4 markedly exerted a dose-dependent inhibition of TNF-α, IL-1ß, IL-6 and PGE2 release induced by LPS in RAW 264.7 macrophages. Moreover, these compounds strongly inhibited LPS-induced NO, COX-2 and iNOS mRNA in the same cells. Anti-inflammatory activity tests in vivo showed that L1 and L4 were more effective than Au(L3)(PPh3), a known anti-inflammatory agent, at 2-5 h, and W4 was the most effective at 3-5 h after dosing. Thus, W2, W4, and L1, L4, could effectively inhibit LPS-induced inflammatory response in vitro and in vivo suggesting a promising role as anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/síntese química , Desenho de Drogas , Inflamação/tratamento farmacológico , Purinas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Citocinas/genética , Citocinas/metabolismo , Edema/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Mediadores da Inflamação/análise , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Camundongos , Purinas/síntese química , Purinas/uso terapêutico , Células RAW 264.7 , RNA Mensageiro/análise , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA