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1.
RSC Adv ; 13(31): 21127-21137, 2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37449028

RESUMO

A new, simple, and efficient method for synthesis of α-benzyl amino coumarin and its derivatives (1-24) is described via a one-pot, three-component condensation of aromatic aldehydes, amine, and 4-hydroxycoumarin under green chemistry conditions: water as a solvent and BaSiO3 nanoparticles as catalyst. BaSiO3 nanoparticles and all synthesized derivatives were characterized by multiple methods including; XRD, NMR, and FE-SEM. This method which gives higher yields, is also less expensive, and more environmentally friendly compared with other methods in the literature. In silico physicochemical and pharmacokinetics analyses were done on all synthesized compounds and indicated that these α-benzyl amino coumarins would be effective scaffolds for the future development of chemotherapeutic agents.

2.
Mol Cancer Ther ; 7(11): 3546-55, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19001437

RESUMO

Evasion of death receptor ligand-induced apoptosis is an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule N-[4-chloro-3-(trifluoromethyl)phenyl]-3-oxobutanamide (fasentin) was identified as a chemical sensitizer to the death receptor stimuli FAS and tumor necrosis factor apoptosis-inducing ligand, but its mechanism of action was unknown. Here, we determined that fasentin alters expression of genes associated with nutrient and glucose deprivation. Consistent with this finding, culturing cells in low-glucose medium recapitulated the effects of fasentin and sensitized cells to FAS. Moreover, we showed that fasentin inhibited glucose uptake. Using virtual docking studies with a homology model of the glucose transport protein GLUT1, fasentin interacted with a unique site in the intracellular channel of this protein. Additional chemical studies with other GLUT inhibitors and analogues of fasentin supported a role for partial inhibition of glucose transport as a mechanism to sensitize cells to death receptor stimuli. Thus, fasentin is a novel inhibitor of glucose transport that blocks glucose uptake and highlights a new mechanism to sensitize cells to death ligands.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Apoptose , Glucose/metabolismo , Receptor fas/metabolismo , Anilidas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Transporte Biológico/efeitos dos fármacos , Ciclo Celular , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Perfilação da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/metabolismo , Humanos , Masculino , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
3.
Apoptosis ; 13(6): 748-55, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18415680

RESUMO

Quinolines are a class of chemical compounds with emerging anti-cancer properties. Here, we tested the activity of series of quinolines and quinoline-like molecules for anti-cancer activity and identified a novel diquinoline, 1-methyl-2-[3-(1-methyl-1,2-dihydroquinolin-2-yliden)prop-1-enyl]quinolinium iodide (Q(2)). Q(2 )induced cell death in leukemia, myeloma, and solid tumor cell lines with LD50s in the low to submicromolar range. Moreover, Q(2) induced cell death in primary acute myeloid leukemia (AML) cells preferentially over normal hematopoietic cells. In a mouse model of leukemia, Q(2) delayed tumor growth. Mechanistically, Q(2) induced cell death through caspase independent mechanisms. By electron microscopy, Q(2) increased cytoplasmic vacuolization and mitochondrial swelling. Potentially consistent with the induction of autophagic cell death, Q(2) treatment led to a punctate distribution of LC3 and increased MDC staining. Thus, Q(2) is a novel quinolinium with preclinical activity in malignancies such as leukemia and myeloma and warrants further investigation.


Assuntos
Morte Celular/efeitos dos fármacos , Compostos de Quinolínio/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Caspases/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Células Jurkat , Dose Letal Mediana , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Camundongos Endogâmicos DBA , Compostos de Quinolínio/uso terapêutico , Células Tumorais Cultivadas , Células U937
4.
Clin Cancer Res ; 12(18): 5557-69, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17000693

RESUMO

PURPOSE: This study aims to identify a novel therapeutic agent for head and neck cancer and to evaluate its antitumor efficacy. EXPERIMENTAL DESIGN: A cell-based and phenotype-driven high-throughput screening of approximately 2,400 biologically active or clinically used compounds was done using a tetrazolium-based assay on FaDu (hypopharyngeal squamous cancer) and NIH 3T3 (untransformed mouse embryonic fibroblast) cells, with secondary screening done on C666-1 (nasopharyngeal cancer) and GM05757 (primary normal human fibroblast) lines. The "hit" compound was assayed for efficacy in combination with standard therapeutics on a panel of human cancer cell lines. Furthermore, its mode of action (using transmission electron microscopy and flow cytometry) and its in vivo efficacy (using xenograft models) were evaluated. RESULTS: Benzethonium chloride was identified as a novel cancer-specific compound. For benzethonium (48-hour incubation), the dose required to reduce cell viability by 50% was 3.8 micromol/L in FaDu, 42.2 micromol/L in NIH 3T3, 5.3 micromol/L in C666-1, and 17.0 micromol/L in GM05757. In vitro, this compound did not interfere with the effects of cisplatin, 5-fluorouracil, or gamma-irradiation. Benzethonium chloride induced apoptosis and activated caspases after 12 hours. Loss of mitochondrial membrane potential (DeltaPsiM) preceded cytosolic Ca2+ increase and cell death. In vivo, benzethonium chloride ablated the tumor-forming ability of FaDu cells, delayed the growth of xenograft tumors, and combined additively with local tumor radiation therapy. Evaluation of benzethonium chloride on the National Cancer Institute/NIH Developmental Therapeutics Program 60 human cancer cell lines revealed broad-range antitumor activity. CONCLUSIONS: This high-throughput screening identified a novel antimicrobial compound with significant broad-spectrum anticancer activity.


Assuntos
Antineoplásicos/isolamento & purificação , Benzetônio/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Análise Serial de Tecidos/métodos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzetônio/farmacologia , Benzetônio/uso terapêutico , Cálcio/metabolismo , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Membranas Mitocondriais/efeitos dos fármacos , Modelos Biológicos , Células NIH 3T3 , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
5.
Org Lett ; 7(6): 1161-4, 2005 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-15760164

RESUMO

[reaction: see text] Straightforward methods for palladium-catalyzed alkenylation of aziridines with alkenyl halides and copper-catalyzed alkenylation of aziridines with alkenyl boronic acids have been developed. This methodology offers attractive alternatives to the known methods requiring activated alkenyl halides and acetylenes. A wide variety of N-alkenyl aziridines containing substituents other than electron-withdrawing substituents such as cyano groups and sulfones have been synthesized in good yields. Furthermore, these N-alkenyl aziridines exhibit quite a different reactivity from conventional enamines, as demonstrated by their reactivity.

6.
Org Lett ; 4(15): 2597-600, 2002 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-12123385

RESUMO

[reaction: see text] A new class of cyclohexane-based P,N-ligands is readily obtained through aziridine ring opening with suitable phosphorus nucleophiles under acidic conditions. trans-1-Amino-2-diphenylphosphinocyclohexane is resolved with tartaric acid to give the final product in >99% ee. The new ligands show high stability toward oxidation at the phosphorus atom.

7.
Mol Cancer Ther ; 9(1): 246-56, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20053768

RESUMO

Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Neoplasias/enzimologia , Neoplasias/patologia , Receptores de Morte Celular/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Técnicas de Silenciamento de Genes , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/farmacologia , Ligantes , Modelos Moleculares , Receptor fas/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-16304383

RESUMO

The IAPs (inhibitor of apoptosis proteins) are a family of caspase inhibitors that block the execution phase of apoptosis. Overexpression of IAPs confers chemoresistance and, in some groups of patients, is associated with a poor prognosis. Given their role in the development and progression of solid tumors and hematologic malignancies, efforts are underway to develop therapeutic IAP inhibitors, with a focus on X-linked IAP (XIAP) and survivin. Antisense oligonucleotides that target XIAP and survivin have been developed and are currently in phase I clinical trial. Small-molecules that bind and inhibit XIAP have also been identified and are in the process of clinical development. This review focuses on the preclinical data that support the development of IAP-targeted therapies.


Assuntos
Proteínas Inibidoras de Apoptose/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Divisão Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/uso terapêutico , Humanos , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/uso terapêutico , Neoplasias/patologia , Oligonucleotídeos Antissenso/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , Survivina , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/uso terapêutico
9.
J Org Chem ; 68(5): 2045-7, 2003 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-12608835

RESUMO

A range of N-arylaziridines were prepared by the palladium or copper catalyzed amination reaction between N-H aziridines and aryl bromides or arylboronic acids. These results showcase the synthetic utility of metal-bound aziridine species in nitrogen transfer processes.

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