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1.
Nano Lett ; 19(10): 7365-7369, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31538793

RESUMO

Biomembranes are hard to compress laterally, and membrane area compressibility has not been associated with biological processes. Using X-ray surface scattering, we observed that bacterial Shiga toxin compresses lipid packing in a gel phase monolayer upon binding to its cellular receptor, the glycolipid Gb3. This toxin-induced reorganization of lipid packing reached beyond the immediate membrane patch that the protein was bound to, and linkers separating the Gb3 carbohydrate and ceramide moieties modulated the toxin's capacity to compress the membrane. Within a natural membrane, asymmetric compression of the toxin-bound leaflet could provide a mechanism to initiate narrow membrane bending, as observed upon toxin entry into cells. Such lipid compression and long-range membrane reorganization by glycolipid-binding proteins represent novel concepts in membrane biology that have direct implications for the construction of endocytic pits in clathrin-independent endocytosis.


Assuntos
Membrana Celular/metabolismo , Fosfatidiletanolaminas/metabolismo , Toxina Shiga/metabolismo , Shigella dysenteriae/metabolismo , Triexosilceramidas/metabolismo , Disenteria Bacilar/metabolismo , Endocitose , Humanos , Modelos Moleculares
2.
Chembiochem ; 20(7): 968-973, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30803119

RESUMO

Chemical Biology is the science of designing chemical tools to dissect and manipulate biology at different scales. It provides the fertile ground from which to address important problems of our society, such as human health and environment.


Assuntos
Biologia , Química , Humanos , Paris
4.
ACS Nano ; 11(1): 314-324, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-27943675

RESUMO

The bacterial Shiga toxin interacts with its cellular receptor, the glycosphingolipid globotriaosylceramide (Gb3 or CD77), as a first step to entering target cells. Previous studies have shown that toxin molecules cluster on the plasma membrane, despite the apparent lack of direct interactions between them. The precise mechanism by which this clustering occurs remains poorly defined. Here, we used vesicle and cell systems and computer simulations to show that line tension due to curvature, height, or compositional mismatch, and lipid or solvent depletion cannot drive the clustering of Shiga toxin molecules. By contrast, in coarse-grained computer simulations, a correlation was found between clustering and toxin nanoparticle-driven suppression of membrane fluctuations, and experimentally we observed that clustering required the toxin molecules to be tightly bound to the membrane surface. The most likely interpretation of these findings is that a membrane fluctuation-induced force generates an effective attraction between toxin molecules. Such force would be of similar strength to the electrostatic force at separations around 1 nm, remain strong at distances up to the size of toxin molecules (several nanometers), and persist even beyond. This force is predicted to operate between manufactured nanoparticles providing they are sufficiently rigid and tightly bound to the plasma membrane, thereby suggesting a route for the targeting of nanoparticles to cells for biomedical applications.


Assuntos
Membrana Celular/química , Nanopartículas/química , Toxina Shiga/química , Triexosilceramidas/química , Humanos , Eletricidade Estática
5.
Chemistry ; 22(42): 14812-14815, 2016 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-27504988

RESUMO

C(sp)-H Bond activation of acetylene molecule still remains a challenge for synthetic organic chemists. In practice, acetylenes are activated by strong bases and metals. The first example for activating acetylenic protons under base and metal-free conditions is reported here. It involves a general method for synthesizing propargylic derivatives of cotarnine. An array of tetrahydroisoquinolines alkaloids was synthesized by C(sp)-H bond activation of aromatic acetylenes with cotarnine at room temperature. A DFT-based mechanism is proposed for the reaction.

6.
Bioorg Med Chem ; 23(22): 7150-7, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26507432

RESUMO

The main drawback of the anticancer chemotherapy consists in the lack of drug selectivity causing severe side effects. The targeted drug delivery appears to be a very promising strategy for controlling the biodistribution of the cytotoxic agent only on malignant tissues by linking it to tumor-targeting moiety. Here we exploit the natural characteristics of Shiga toxin B sub-unit (STxB) as targeting carrier on Gb3-positive cancer cells. Two cytotoxic conjugates STxB-doxorubicin (STxB-Doxo) and STxB-monomethyl auristatin F (STxB-MMAF) were synthesised using copper-free 'click' chemistry. Both conjugates were obtained in very high yield and demonstrated strong tumor inhibition activity in a nanomolar range on Gb3-positive cells.


Assuntos
Antineoplásicos/química , Química Click , Doxorrubicina/química , Portadores de Fármacos/química , Oligopeptídeos/química , Toxina Shiga/química , Anticorpos/imunologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Doxorrubicina/toxicidade , Portadores de Fármacos/síntese química , Desenho de Fármacos , Células HT29 , Células HeLa , Humanos , Microscopia Confocal , Oligopeptídeos/toxicidade , Toxina Shiga/imunologia , Toxina Shiga/metabolismo
7.
Biophys J ; 107(5): 1146-1155, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25185550

RESUMO

Globotriaosylceramide (Gb3), a glycosphingolipid found in the plasma membrane of animal cells, is the endocytic receptor of the bacterial Shiga toxin. Using x-ray reflectivity (XR) and grazing incidence x-ray diffraction (GIXD), lipid monolayers containing Gb3 were investigated at the air-water interface. XR probed Gb3 carbohydrate conformation normal to the interface, whereas GIXD precisely characterized Gb3's influence on acyl chain in-plane packing and area per molecule (APM). Two phospholipids, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), were used to study Gb3 packing in different lipid environments. Furthermore, the impact on monolayer structure of a naturally extracted Gb3 mixture was compared to synthetic Gb3 species with uniquely defined acyl chain structures. XR results showed that lipid environment and Gb3 acyl chain structure impact carbohydrate conformation with greater solvent accessibility observed for smaller phospholipid headgroups and long Gb3 acyl chains. In general, GIXD showed that Gb3 condensed phospholipid packing resulting in smaller APM than predicted by ideal mixing. Gb3's capacity to condense APM was larger for DSPC monolayers and exhibited different dependencies on acyl chain structure depending on the lipid environment. The interplay between Gb3-induced changes in lipid packing and the lipid environment's impact on carbohydrate conformation has broad implications for glycosphingolipid macromolecule recognition and ligand binding.


Assuntos
Triexosilceramidas/química , Ar , Animais , Configuração de Carboidratos , Eritrócitos/química , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Pressão , Solventes/química , Propriedades de Superfície , Suínos , Água , Difração de Raios X
8.
Biol Aujourdhui ; 207(1): 39-54, 2013.
Artigo em Francês | MEDLINE | ID: mdl-23694724

RESUMO

Obtaining and screening collections of small molecules remain a challenge for biologists. Recent advances in analytical techniques and instrumentation now make screening possible in academia. The history of the creation of such public or commercial collections and their accessibility is related. It shows that there is interest for an academic laboratory involved in medicinal chemistry, chemogenomics or "chemical biology" to organize its own collection and make it available through existing networks such as the French National chimiothèque or the European partner network "European Infrastructure of open screening platforms for Chemical Biology" EU-OpenScreen under construction.


Assuntos
Técnicas de Química Combinatória , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Bibliotecas de Moléculas Pequenas/química , Humanos
9.
Bioorg Med Chem ; 21(5): 1357-66, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23369686

RESUMO

To evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (-)-1b, (-)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities.


Assuntos
Ciclopropanos/química , Estilbenos/química , Moduladores de Tubulina/síntese química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colchicina , Ciclopropanos/síntese química , Ciclopropanos/toxicidade , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidade
10.
Br J Pharmacol ; 168(3): 673-85, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23004938

RESUMO

BACKGROUND AND PURPOSE: Drugs targeting microtubules are commonly used for cancer treatment. However, the potency of microtubule inhibitors used clinically is limited by the emergence of resistance. We thus designed a strategy to find new cell-permeable microtubule-targeting agents. EXPERIMENTAL APPROACH: Using a cell-based assay designed to probe for microtubule polymerization status, we screened a chemical library and identified two azaindole derivatives, CM01 and CM02, as cell-permeable microtubule-depolymerizing agents. The mechanism of the anti-tumour effects of these two compounds was further investigated both in vivo and in vitro. KEY RESULTS: CM01 and CM02 induced G2/M cell cycle arrest and exerted potent cytostatic effects on several cancer cell lines including multidrug-resistant (MDR) cell lines. In vitro experiments revealed that the azaindole derivatives inhibited tubulin polymerization and competed with colchicines for this effect, strongly indicating that tubulin is the cellular target of these azaindole derivatives. In vivo experiments, using a chicken chorioallantoic xenograft tumour assay, established that these compounds exert a potent anti-tumour effect. Furthermore, an assay probing the growth of vessels out of endothelial cell spheroids showed that CM01 and CM02 exert anti-angiogenic activities. CONCLUSIONS AND IMPLICATIONS: CM01 and CM02 are reversible microtubule-depolymerizing agents that exert potent cytostatic effects on human cancer cells of diverse origins, including MDR cells. They were also shown to inhibit angiogenesis and tumour growth in chorioallantoic breast cancer xenografts. Hence, these azaindole derivatives are attractive candidates for further preclinical investigations.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Cultivadas , Embrião de Galinha , Membrana Corioalantoide/patologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Humanos , Indóis/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Moduladores de Tubulina/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cell Mol Life Sci ; 70(4): 729-42, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23007843

RESUMO

Links between cancer and stem cells have been proposed for many years. As the cancer stem cell (CSC) theory became widely studied, new methods were developed to culture and expand cancer cells with conserved determinants of "stemness". These cells show increased ability to grow in suspension as spheres in serum-free medium supplemented with growth factors and chemicals. The physiological relevance of this phenomenon in established cancer cell lines remains unclear. Cell lines have traditionally been used to explore tumor biology and serve as preclinical models for the screening of potential therapeutic agents. Here, we grew cell-forming spheres (CFS) from 25 established colorectal cancer cell lines. The molecular and cellular characteristics of CFS were compared to the bulk of tumor cells. CFS could be isolated from 72 % of the cell lines. Both CFS and their parental CRC cell lines were highly tumorigenic. Compared to their parental cells, they showed similar expression of putative CSC markers. The ability of CRC cells to grow as CFS was greatly enhanced by prior treatment with 5-fluorouracil. At the molecular level, CFS and parental CRC cells showed identical gene mutations and very similar genomic profiles, although microarray analysis revealed changes in CFS gene expression that were independent of DNA copy-number. We identified a CFS gene expression signature common to CFS from all CRC cell lines, which was predictive of disease relapse in CRC patients. In conclusion, CFS models derived from CRC cell lines possess interesting phenotypic features that may have clinical relevance for drug resistance and disease relapse.


Assuntos
Neoplasias Colorretais/patologia , Esferoides Celulares/patologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia , Reto/efeitos dos fármacos , Reto/metabolismo , Reto/patologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Células Tumorais Cultivadas
12.
Cancer Res ; 72(17): 4429-39, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22761334

RESUMO

The emergence of tumor resistance to conventional microtubule-targeting drugs restricts their clinical use. Using a cell-based assay that recognizes microtubule polymerization status to screen for chemicals that interact with regulators of microtubule dynamics, we identified Pyr1, a cell permeable inhibitor of LIM kinase, which is the enzyme that phosphorylates and inactivates the actin-depolymerizing factor cofilin. Pyr1 reversibly stabilized microtubules, blocked actin microfilament dynamics, inhibited cell motility in vitro and showed anticancer properties in vivo, in the absence of major side effects. Pyr1 inhibition of LIM kinase caused a microtubule-stabilizing effect, which was independent of any direct effects on the actin cytoskeleton. In addition, Pyr1 retained its activity in multidrug-resistant cancer cells that were resistant to conventional microtubule-targeting agents. Our findings suggest that LIM kinase functions as a signaling node that controls both actin and microtubule dynamics. LIM kinase may therefore represent a targetable enzyme for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Quinases Lim/antagonistas & inibidores , Microtúbulos/metabolismo , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Moduladores de Tubulina/farmacologia , Actinas/metabolismo , Animais , Antineoplásicos/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HeLa , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Fenótipo , Inibidores de Proteínas Quinases/administração & dosagem , Estabilidade Proteica/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/administração & dosagem
13.
Traffic ; 13(7): 914-25, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22443104

RESUMO

Proteomics is a powerful technique for protein identification at large scales. A number of proteomics approaches have been developed to study the steady state composition of intracellular compartments. Here, we report a novel vectorial proteomics strategy to identify plasma membrane proteins that undergo retrograde transport to the trans-Golgi network (TGN). This strategy is based on the covalent modification of the plasma membrane proteome with a membrane impermeable benzylguanine derivative. Benzylguanine-tagged plasma membrane proteins that are subsequently targeted to the retrograde route are covalently captured by a TGN-localized SNAP-tagged fusion protein, which allows for their identification. The approach was validated step-by-step using a well explored retrograde cargo protein, the B-subunit of Shiga toxin. It was then extended to the proteomics format. Among other hits we found one of the historically first identified cargo proteins that undergo retrograde transport, which further validated our approach. Most of the other hits were kinases, receptors or transporters. In conclusion, we have pioneered a vectorial proteomics approach that complements traditional methods for the study of retrograde protein trafficking. This approach is of generic nature and could in principle be extended to other endocytic pathways.


Assuntos
Proteínas de Membrana/metabolismo , Proteoma/análise , Proteômica/métodos , Animais , Endocitose/fisiologia , Guanina/análogos & derivados , Guanina/química , Células HeLa , Humanos , Espectrometria de Massas , Proteínas de Membrana/análise , Transporte Proteico , Receptores da Transferrina/análise , Proteínas SNARE/genética , Toxina Shiga/análise
14.
Org Biomol Chem ; 10(13): 2683-91, 2012 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-22362022

RESUMO

An original tribromide derivative based, palladium-catalyzed synthesis of 3-substituted-1(2H)-isoquinolone is described based on a regioselective Suzuki-Miyaura C-C coupling on o-halo-(2,2-dihalovinyl)-benzene followed by a palladium catalyzed amination-carbonylation-cyclization reaction. This sequence efficiently proceeds to build up isoquinolone in fair to good yields over a one-pot 3-bond synthesis reaction.

15.
J Org Chem ; 77(3): 1316-27, 2012 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-22141919

RESUMO

An efficient access to 2-substituted 3-arylbenzofurans through a palladium-catalyzed C3 direct arylation of 2-substituted benzofurans with aryl bromides is described. The scope and limitation of this reaction was studied. The method tolerates a variety of functional groups on the aryl halide and has been successfully extended to polysubstituted benzofurans to obtain the corresponding 3-arylbenzofurans with good to excellent yields.


Assuntos
Benzofuranos/química , Paládio/química , Catálise , Transporte de Elétrons
16.
ChemMedChem ; 6(9): 1693-705, 2011 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-21732536

RESUMO

A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Células Endoteliais/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Estilbenos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Catálise , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Compostos Heterocíclicos/química , Humanos , Camundongos , Paládio/química , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo
17.
J Org Chem ; 76(8): 2502-20, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21391629

RESUMO

The synthesis of novel 3-aryl-2-arylamidobenzofurans has been accomplished via a Curtius rearrangement strategy in four steps from benzofuran-2-carboxylic acids. The requisite Suzuki-Miyaura cross-coupling, with benzyl 3-bromobenzofuran-2-ylcarbamate or 2-arylamido-3-bromobenzofurans, revealed an unusual reductive debromination process due to the presence of the free NH group. This dehalogenation can be suppressed by N-alkylation. DMAP is an efficient reagent for the one-pot conversion of benzyl benzofuran-2-ylcarbamates into the corresponding benzofuran-2-arylamides through aroylation, thus acting both as an acyl transfer reagent and a deprotecting agent of the Cbz group. A mechanism is postulated.


Assuntos
Benzofuranos/síntese química , Produtos Biológicos/síntese química , Química Farmacêutica/métodos , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/química , Alquilação , Amidas/química , Aminas/química , Ácidos Borônicos/química , Ácidos Carboxílicos/química , Catálise , Estereoisomerismo
18.
J Colloid Interface Sci ; 357(1): 75-81, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21334635

RESUMO

We have investigated the most efficient way of preparing biocompatible gold nanorods (GNR) used as tool for cancer imaging and therapy. The surface of cetyltrimethylammonium bromide-stabilized gold nanorods (GNR-CTAB) was functionalized with various thio-polyethylene glycols of the general formula HS-PEGmX (m=356-10,000; X=-OMe, -NH(2)). The influence of several parameters such as PEG chain length, reaction conditions and purification method on long-term stability, morphology and optical properties of the produced GNR-S-PEGmX was studied, demonstrating the existence of a threshold HS-PEGmX chain length (with molecular weight m≥2000) for efficient steric stabilization of GNR. Several purification techniques were compared: dialysis, centrifugation and a rarely used technique in this field, size exclusion chromatography. While a very weak efficiency of dialysis was evidenced, both centrifugation and size exclusion chromatography were found to provide pure GNRs, though the latter method yielded nanoparticles with a significantly higher stability. Finally, the long-term stability of the produced GNRs was investigated in various media: water, PBS buffer and serum.


Assuntos
Diagnóstico por Imagem/métodos , Ouro/química , Nanotubos/química , Neoplasias/patologia , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/isolamento & purificação , Estabilidade de Medicamentos , Polietilenoglicóis/química
19.
Eur J Med Chem ; 46(1): 95-100, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21112130

RESUMO

Two series of 2-aroyltrimethoxyindoles were designed to investigate the effects of the replacement of the trimethoxyphenyl ring of phenstatin with a trimethoxyindole moiety. These compounds were efficiently prepared through a domino palladium-catalyzed sequence from 2-gem-dibromovinylanilines substituted by three methoxy groups and arylboronic acids under carbon monoxide atmosphere. These novel heterocyclic combretastatin A4 analogues were evaluated for their cell growth inhibitory properties and their ability to inhibit the tubulin polymerization.


Assuntos
Descoberta de Drogas/métodos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Indóis/química , Indóis/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Tubulina (Proteína)/química
20.
Cancer Res ; 70(23): 9865-74, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21118972

RESUMO

The alkyloid compound ellipticine derived from the berrywood tree is a topoisomerase II poison that is used in ovarian and breast cancer treatment. In this study, we report the identification of ellipticine derivatives and their tetracyclic angular benzopyridoindole analogues as novel ATP-competitive inhibitors of the protein kinase CK2. In vitro and in vivo assays showed that these compounds have a good pharmacologic profile, causing a marked inhibition of CK2 activity associated with cell cycle arrest and apoptosis in human cancer cells. Further, in vivo assays demonstrate antitumor activity in a mouse xenograft model of human glioblastoma. Finally, crystal structures of CK2-inhibitor complex provide structural insights on the molecular basis of CK2 inhibition. Our work lays the foundation for development of clinically useful CK2 inhibitors derived from a well-studied scaffold with suitable pharmacokinetics parameters.


Assuntos
Antineoplásicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Elipticinas/farmacologia , Neoplasias/tratamento farmacológico , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Western Blotting , Carbazóis/química , Carbazóis/farmacologia , Caseína Quinase II/química , Caseína Quinase II/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Elipticinas/química , Feminino , Células HeLa , Humanos , Indóis/química , Indóis/farmacologia , Cinética , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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