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1.
Bioorg Med Chem ; 22(4): 1450-8, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24457091

RESUMO

A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.


Assuntos
Antineoplásicos/química , Nitrilas/química , Piridinas/química , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cianoacrilatos , Dimerização , Humanos , Modelos Moleculares , Mieloma Múltiplo/tratamento farmacológico , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo
2.
Bioorg Med Chem ; 22(1): 623-32, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24280068

RESUMO

We synthesized two series of imatinib mesylate (STI-571) analogs to develop a Bcr-Abl and c-KIT receptor-specific labeling agent for positron emission tomography (PET) imaging to measure Bcr-Abl and c-KIT expression levels in a mouse model. The methods of molecular modeling, synthesis of STI-571 and its analogs, in vitro kinase assays, and radiolabeling are described. Molecular modeling revealed that these analogs bind the same Bcr-Abl and c-KIT binding sites as those bound by STI-571. The analogs potently inhibit the tyrosine kinase activity of Bcr-Abl and c-KIT, similarly to STI-571. [(18)F]-labeled STI-571 was prepared with high specific activity (75 GBq/µmol) by nucleophilic displacement and an average radiochemical yield of 12%. [(131)I]-labeled STI-571 was prepared with high purity (>95%) and an average radiochemical yield of 23%. The uptake rates of [(18)F]-STI-571 in K562 cells expressing Abl and in U87WT cells overexpressing c-KIT were significantly higher than those in the U87 cell and could be inhibited by STI-71 (confirming the specificity of uptake). PET scans of K562 and U87WT tumor-bearing mice with [(18)F]-STI-571 as a contrast agent showed visible tumor uptake and tumor-to-non-target contrast.


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Proteínas de Fusão bcr-abl/metabolismo , Piperazinas/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/química , Benzamidas/química , Modelos Animais de Doenças , Humanos , Mesilato de Imatinib , Camundongos , Modelos Moleculares , Piperazinas/química , Pirimidinas/química
3.
Bioorg Med Chem ; 21(17): 5182-7, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23859776

RESUMO

An improved method for the synthesis of 17ß-hydroxy-16α-iodo-wortmannin along with the first synthesis of 17ß-hydroxy-16α-iodoPX866 and [(131)I] radiolabeled 17ß-hydroxy-16α-[(131)I]iodo-wortmannin, as potential PET tracers for PI3K was also described. The differences between wortmannin and its iodo analogue were compared by covalently docking each structure to L833 in PI3K.


Assuntos
Androstadienos/química , Androstadienos/síntese química , Gonanos/síntese química , Compostos Radiofarmacêuticos/síntese química , Sítios de Ligação , Gonanos/química , Radioisótopos do Iodo/química , Marcação por Isótopo , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinase/química , Fosfatidilinositol 3-Quinase/metabolismo , Tomografia por Emissão de Pósitrons , Estrutura Terciária de Proteína , Compostos Radiofarmacêuticos/química , Wortmanina
4.
Bioorg Med Chem ; 21(4): 932-9, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23294827

RESUMO

Curcumin (diferuloylmethane) is a potent anti-inflammatory and anti-tumorigenic agent that has shown preclinical activity in diverse cancers. Curcumin up-regulates heat shock protein 70 (hsp70) mRNA in several different cancer cell lines. Hsp70 contributes to an escape from the apoptotic effects of curcumin by several different mechanisms including prevention of the release of apoptosis inducing factor from the mitochondria and inhibition of caspases 3 and 9. Previously we showed that the combination of curcumin plus a heat shock protein inhibitor was synergistic in its down-regulation of the proliferation of a human schwannoma cell line (HEI-193) harboring an NF2 mutation, possibly because curcumin up-regulated hsp70, which also binds merlin, the NF2 gene product. In order to determine if curcumin also interacts directly with hsp70 and to discover other binding partners of curcumin, we synthesized biotinylated curcumin (bio-curcumin) and treated HEI-193 schwannoma cells. Cell lysates were prepared and incubated with avidin-coated beads. Peptides pulled down from this reaction were sequenced and it was determined that biotinylated curcumin bound hsp70, hsp90, 3-phosphoglycerate dehydrogenase, and a ß-actin variant. These binding partners may serve to further elucidate the underlying mechanisms of curcumin's actions.


Assuntos
Curcumina/química , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP90/química , Fosfoglicerato Desidrogenase/química , Sítios de Ligação , Biotina/química , Linhagem Celular Tumoral , Curcumina/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Simulação de Acoplamento Molecular , Neurilemoma/metabolismo , Neurilemoma/patologia , Fosfoglicerato Desidrogenase/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína
5.
Mol Cancer Ther ; 12(5): 654-62, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23303403

RESUMO

We have previously shown that the antiallergic drug cromolyn blocks S100P interaction with its receptor receptor for advanced glycation end product (RAGE) and improves gemcitabine effectiveness in pancreatic ductal adenocarcinoma (PDAC). However, the concentration required to achieve its effectiveness was high (100 µmol/L). In this study, we designed and synthesized analogs of cromolyn and analyzed their effectiveness compared with the parent molecule. An ELISA was used to confirm the binding of S100P with RAGE and to test the effectiveness of the different analogs. Analog 5-methyl cromolyn (C5OH) blocked S100P binding as well as the increases in NF-κB activity, cell growth, and apoptosis normally caused by S100P. In vivo C5OH systemic delivery reduced NF-κB activity to a greater extent than cromolyn and at 10 times lesser dose (50 mg vs. 5 mg). Treatment of mice-bearing syngeneic PDAC tumors showed that C5OH treatment reduced both tumor growth and metastasis. C5OH treatment of nude mice bearing orthotopic highly aggressive pancreatic Mpanc96 cells increased the overall animal survival. Therefore, the cromolyn analog, C5OH, was found to be more efficient and potent than cromolyn as a therapeutic for PDAC.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Carcinoma Ductal Pancreático/metabolismo , Cromolina Sódica/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Pancreáticas/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromolina Sódica/análogos & derivados , Cromolina Sódica/química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Camundongos Nus , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Ligação Proteica/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Nucl Med ; 50(3): 409-16, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19223410

RESUMO

UNLABELLED: Imaging 2 different molecular-genetic events in a single subject by PET is essential in a variety of in vivo applications. Using herpes simplex virus-1 thymidine kinase (HSV1-tk) mutants with narrower substrate specificities in combination with wild-type HSV1-tk (wtHSV1-tk) would enable differential imaging with corresponding radiotracers, namely 2'-deoxy-2'-(18)F-fluoro-5-ethyl-1-beta-d-arabinofuranosyl-uracil ((18)F-FEAU) and the acycloguanosine derivative 9-(4-(18)F-fluoro-3-[hydroxymethyl]butyl)guanine ((18)F-FHBG). In this study, we evaluated wtHSV1-tk and the A168H mutant, which has been reported to exhibit enhanced acycloguanosine substrate catalytic activity and diminished pyrimidine phosphorylating activity, as PET reporter genes. METHODS: Computational analysis was performed to assess the binding mode of FHBG and FEAU to wtHSV1-tk and the A168H variant. U87 cells were stably transduced with wtHSV1-tk or HSV1-tk(A168H) fused with green fluorescent protein and sorted to obtain equivalent transgene expression. In vitro uptake studies were performed to determine rates of substrate accumulation and retention. Nude mice bearing tumors expressing HSV1-tk variants were subsequently imaged using (18)F-FHBG and (18)F-FEAU. RESULTS: Docking results indicate that binding of FHBG to the A168H variant is unaffected whereas the binding of FEAU is hindered because of a steric clash with the bulkier mutant residues. U87 cells expressing HSV1-tk(A168H) accumulated (18)F-FHBG in in vitro uptake studies at a 3-fold higher rate than did cells expressing wtHSV1-tk without any detectable accumulation of (3)H-FEAU. Furthermore, HSV1-tk(A168H) demonstrated no thymidine phosphorylation activity. In contrast, U87 cells expressing wtHSV1-tk preferentially accumulated (3)H-FEAU at an 18-fold higher rate than they did (18)F-FHBG. Tumors expressing wtHSV1-tk or HSV1-tk(A168H) were distinctly imaged with (18)F-FEAU or (18)F-FHBG, respectively. Hence, tumors expressing HSV1-tk(A168H) accumulated 8.4-fold more (18)F-FHBG than did tumors expressing wtHSV1-tk. In addition, wtHSV1-tk tumors, compared with HSV1-tk(A168H)-expressing tumors (which retained baseline levels of the radiotracer), preferentially accumulated (18)F-FEAU. CONCLUSION: The FEAU and FHBG substrate discrimination capacity of the wtHSV1-tk and HSV1-tk(A168H) reporter enzymes was validated in vivo by PET of mice with tumor xenografts established from U87 cells expressing these different reporters. Thus, HSV1-tk(A168H) may potentially be used as a second reporter gene in combination with wtHSV1-tk to achieve differential PET.


Assuntos
Arabinofuranosiluracila/análogos & derivados , Fluoruracila/análogos & derivados , Guanina/análogos & derivados , Herpesvirus Humano 1/enzimologia , Compostos Radiofarmacêuticos , Timidina Quinase/metabolismo , Animais , Arabinofuranosiluracila/química , Linhagem Celular Tumoral , Estudos de Viabilidade , Radioisótopos de Flúor , Fluoruracila/química , Genes Reporter , Guanina/química , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Mutação , Transplante de Neoplasias , Tomografia por Emissão de Pósitrons , Ligação Proteica , Compostos Radiofarmacêuticos/química , Relação Estrutura-Atividade , Timidina Quinase/química , Timidina Quinase/genética , Transplante Heterólogo
7.
Mol Cancer Ther ; 5(5): 1325-34, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16731766

RESUMO

Histone deacetylase (HDAC) inhibitors are new and promising antineoplastic agents. Current methods for monitoring early response rely on invasive biopsies or indirect blood-derived markers. Our goal was to develop a magnetic resonance spectroscopy (MRS)-based method to detect HDAC inhibition. The fluorinated lysine derivative Boc-Lys-(Tfa)-OH (BLT) was investigated as a (19)F MRS molecular marker of HDAC activity together with (31)P MRS of endogenous metabolites. In silico modeling of the BLT-HDAC interaction and in vitro MRS studies of BLT cleavage by HDAC confirmed BLT as a HDAC substrate. BLT did not affect cell viability or HDAC activity in PC3 prostate cancer cells. PC3 cells were treated, in the presence of BLT, with the HDAC inhibitor p-fluoro-suberoylanilide hydroxamic acid (FSAHA) over the range of 0 to 10 micromol/L, and HDAC activity and MRS spectra were monitored. Following FSAHA treatment, HDAC activity dropped, reaching 53% of control at 10 micromol/L FSAHA. In parallel, a steady increase in intracellular BLT from 14 to 32 fmol/cell was observed. BLT levels negatively correlated with HDAC activity consistent with higher levels of uncleaved BLT in cells with inhibited HDAC. Phosphocholine, detected by (31)P MRS, increased from 7 to 16 fmol/cell following treatment with FSAHA and also negatively correlated with HDAC activity. Increased phosphocholine is probably due to heat shock protein 90 inhibition as indicated by depletion of client proteins. In summary, (19)F MRS of BLT, combined with (31)P MRS, can be used to monitor HDAC activity in cells. In principle, this could be applied in vivo to noninvasively monitor HDAC activity.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Histona Desacetilases/química , Espectroscopia de Ressonância Magnética/métodos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Quinase 4 Dependente de Ciclina/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Histona Desacetilases/metabolismo , Humanos , Lisina/análogos & derivados , Lisina/metabolismo , Lisina/farmacologia , Isótopos de Fósforo , Fosforilcolina/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , Células Tumorais Cultivadas
8.
Expert Rev Anticancer Ther ; 6(2): 175-86, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16445370

RESUMO

Protein kinase (PK)Calpha and epsilon are rational targets for cancer therapy. However, targeted experimental therapeutics that inhibit PKCalpha or epsilon are unavailable. The authors established recently that covalent modification of an active-site cysteine in human PKCepsilon, Cys452, by small molecules, for example 2-mercaptoethanolamine, is necessary and sufficient to render PKCepsilon kinase-dead. Cys452 is conserved in only eleven human protein kinase genes, including PKCalpha. Therefore, the design of small molecules that bind PKC active sites with an electrophile substituent positioned proximal to the Cys452 side chain may lead to targeted therapeutics that selectively inhibit PKCepsilon, PKCalpha or other PKC isozymes.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C-épsilon/antagonistas & inibidores , Proteína Quinase C-épsilon/metabolismo , Antineoplásicos/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia
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