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1.
J Am Chem Soc ; 139(42): 15022-15032, 2017 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-29022341

RESUMO

The Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) is an efficient, redox-neutral method of synthesizing α-acyloxy cyclopentenones. An enantioselective APKR could provide access to chiral, nonracemic α-acyloxy and α-hydroxy cyclopentenones and their corresponding redox derivatives, such as thapsigargin, a cytotoxic natural product with potent antitumor activity. Rapid scrambling of axial chirality of allenyl acetates in the presence of Rh(I) catalysts enables the conversion of racemic allene to enantiopure cyclopentenone product in a dynamic kinetic asymmetric transformation (DyKAT). A combined experimental and computational approach was taken to develop an effective catalytic system to achieve the asymmetric transformation. The optimization of the denticity, and steric and electronic properties of the ancillary ligand (initially (S)-MonoPhos, 58:42 er), afforded a hemilabile bidentate (S)-MonoPhos-alkene-Rh(I) catalyst that provided α-acyloxy cyclopentenone product in up to 14:86 er. Enantioselectivity of the Rh(I)-(S)-MonoPhos-alkene catalyst was rationalized using ligand-substrate steric interactions and distortion energies in the computed transition states. This asymmetric APKR of allenyl acetates is a rare example of a Type I DyKAT reaction of an allene, the first example of DyKAT in a cyclocarbonylation reaction, and the first catalyst-controlled enantioselective APKR.


Assuntos
Acetatos/química , Ciclopentanos/síntese química , Acetatos/síntese química , Alcenos/química , Catálise , Ciclopentanos/química , Cinética , Ligantes , Reprodutibilidade dos Testes , Rodaminas/química , Estereoisomerismo , Tapsigargina/síntese química , Tapsigargina/química
2.
Org Lett ; 19(7): 1500-1503, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28267342

RESUMO

Using an intramolecular didehydro-Diels-Alder reaction, ene-yne substituted pyrroles, thiophenes, and furans afford functionalized indoles, benzothiophenes, and benzofurans and the corresponding dihydroaromatic products. Product selectivity for the aromatic or dihydroaromatic product is controlled by the reaction conditions, which vary depending upon the substrate.

3.
J Med Chem ; 60(3): 839-885, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-27996267

RESUMO

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on α,ß-unsaturated carbonyls given their preponderance in bioactive natural products.


Assuntos
Cetonas/química , Compostos de Sulfidrila/química , Linhagem Celular Tumoral , Desenho de Drogas , Receptores ErbB/efeitos dos fármacos , Humanos
4.
Org Lett ; 18(18): 4566-9, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27570975

RESUMO

The Nicholas reaction has been applied to the installation of alkyne ligation handles. Acid-promoted propargylation of hydroxyl, sulfhydryl, amino, and carboxyl groups using dicobalt hexacarbonyl-stabilized propargylium ions is reported. This method is useful for introduction of propargyl groups into base-sensitive molecules, thereby expanding the toolbox of methods for the incorporation of alkynes for bio-orthogonal reactions. High-value molecules are used as the limiting reagent, and various propargylium ion precursors are compared.


Assuntos
Alquinos/química , Monóxido de Carbono/química , Radical Hidroxila/química , Pargilina/síntese química , Prolina/química , Compostos de Sulfidrila/química , Cobalto/química , Estrutura Molecular , Pargilina/análogos & derivados , Pargilina/química , Prolina/análogos & derivados
5.
Tetrahedron Lett ; 56(23): 3546-3549, 2015 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-26257443

RESUMO

The direct installation of the C4 and C10 methyl groups present in the 6,12-guaianolide framework using a Rh(I)-catalyzed cyclocarbonylation reaction of methyl subsituted allenes and alkynes is described. High yields of bicyclo[5.3.0]decanes are afforded when low reaction concentrations involving syringe pump addition of the allene-yne to the catalyst are used.

6.
Acc Chem Res ; 48(8): 2320-9, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26207414

RESUMO

Reaction discovery plays a vital role in accessing new chemical entities and materials possessing important function.1 In this Account, we delineate our reaction discovery program regarding the [4 + 2] cycloaddition reaction of styrene-ynes. In particular, we highlight our studies that lead to the realization of the diverging reaction mechanisms of the intramolecular didehydro-Diels-Alder (IMDDA) reaction to afford dihydronaphthalene and naphthalene products. Formation of the former involves an intermolecular hydrogen atom abstraction and isomerization, whereas the latter is formed via an unexpected elimination of H2. Forming aromatic compounds by a unimolecular elimination of H2 offers an environmentally benign alternative to typical oxidation protocols. We also include in this Account ongoing work focused on expanding the scope of this reaction, mainly its application to the preparation of cyclopenta[b]naphthalenes. Finally, we showcase the synthetic utility of the IMDDA reaction by preparing novel environmentally sensitive fluorophores. The choice to follow this path was largely influenced by the impact this reaction could have on our understanding of the structure-function relationships of these molecular sensors by taking advantage of a de novo construction and functionalization of the aromatic portion of these compounds. We were also inspired by the fact that, despite the advances that have been made in the construction of small molecule fluorophores, access to rationally designed fluorescent probes or sensors possessing varied and tuned photophysical, spectral, and chemical properties are still needed. To this end, we report our studies to correlate fluorophore structure with photophysical property relationships for a series of solvatochromic PRODAN analogs and viscosity-sensitive cyanoacrylate analogs. The versatility of this de novo strategy for fluorophore synthesis was demonstrated by showing that a number of functional groups could be installed at various locations, including handles for eventual biomolecule attachment or water-solubilizing groups. Further, biothiol sensors were designed, and we expect these to be of general utility for the study of lipid dynamics in cellular membranes and for the detection of protein-binding interactions, ideal applications for these relatively hydrophobic fluorophores. Future studies will be directed toward expanding this chemistry-driven approach to the rational preparation of fluorophores with enhanced photophysical and chemical properties for application in biological systems.


Assuntos
Corantes Fluorescentes/química , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , Cianoacrilatos/química , Reação de Cicloadição , Corantes Fluorescentes/síntese química , Hidrogênio/química , Naftalenos/química , Relação Estrutura-Atividade , Viscosidade
7.
J Org Chem ; 80(23): 11686-98, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25671399

RESUMO

The Diels-Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels-Alder (IMDDA) reactions have previously been employed for the preparation of naphthalene and dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA reaction of styrene-ynes produces a naphthalene product via loss of hydrogen gas from the initially formed cycloadduct, a tetraenyl intermediate. Alternatively, the dihydronaphthalene product is afforded from the same tetraenyl intermediate via a radical isomerization process. Moreover, we have identified conditions that can be used to achieve efficient, high-yielding, and selective IMDDA reactions of styrene-ynes to form either naphthalene or dihydronaphthalene products. The operational simplicity and retrosynthetic orthogonality of this method for the preparation of naphthalenes and dihydronaphthalenes makes this transformation appealing for the synthesis of medicinal and material targets. The mechanistic studies within may impact the development of other thermal transformations.


Assuntos
Naftalenos/química , Estireno/química , Reação de Cicloadição , Estrutura Molecular , Estereoisomerismo , Temperatura Ambiente
8.
Org Biomol Chem ; 13(10): 2965-73, 2015 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-25614187

RESUMO

We describe the design, synthesis and fluorescent profile of a family of environment-sensitive dyes in which a dimethylamino (donor) group is conjugated to a cyanoacrylate (acceptor) unit via a cyclopenta[b]naphthalene ring system. This assembly satisfies the typical D-π-A motif of a fluorescent molecular rotor and exhibits solvatochromic and viscosity-sensitive fluorescence emission. The central naphthalene ring system of these dyes was synthesized via a novel intramolecular dehydrogenative dehydro-Diels-Alder (IDDDA) reaction that permits incorporation of the donor and acceptor groups in variable positions around the aromatic core. A bathochromic shift of excitation and emission peaks was observed with increasing solvent polarity but the dyes exhibited a complex emission pattern with a second red emission band when dissolved in nonpolar solvents. Consistent with other known molecular rotors, the emission intensity increased with increasing viscosity. Interestingly, closer spatial proximity between the donor and the acceptor groups led to decreased viscosity sensitivity combined with an increased quantum yield. This observation indicates that structural hindrance of intramolecular rotation dominates when the donor and acceptor groups are in close proximity. The examined compounds give insight into how excited state intramolecular rotation can be influenced by both the solvent and the chemical structure.


Assuntos
Cianoacrilatos/química , Corantes Fluorescentes/química , Naftalenos/química , Reação de Cicloadição , Desenho de Drogas , Fluorescência , Estrutura Molecular , Solventes/química , Espectrometria de Fluorescência , Viscosidade
9.
Cancer Res ; 74(24): 7534-45, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25336189

RESUMO

Resistance to DNA-damaging chemotherapy is a barrier to effective treatment that appears to be augmented by p53 functional deficiency in many cancers. In p53-deficient cells in which the G1-S checkpoint is compromised, cell viability after DNA damage relies upon intact intra-S and G2-M checkpoints mediated by the ATR (ataxia telangiectasia and Rad3 related) and Chk1 kinases. Thus, a logical rationale to sensitize p53-deficient cancers to DNA-damaging chemotherapy is through the use of ATP-competitive inhibitors of ATR or Chk1. To discover small molecules that may act on uncharacterized components of the ATR pathway, we performed a phenotype-based screen of 9,195 compounds for their ability to inhibit hydroxyurea-induced phosphorylation of Ser345 on Chk1, known to be a critical ATR substrate. This effort led to the identification of four small-molecule compounds, three of which were derived from known bioactive library (anthothecol, dihydrocelastryl, and erysolin) and one of which was a novel synthetic compound termed MARPIN. These compounds all inhibited ATR-selective phosphorylation and sensitized p53-deficient cancer cells to DNA-damaging agents in vitro and in vivo. Notably, these compounds did not inhibit ATR catalytic activity in vitro, unlike typical ATP-competitive inhibitors, but acted in a mechanistically distinct manner to disable ATR-Chk1 function. Our results highlight a set of novel molecular probes to further elucidate druggable mechanisms to improve cancer therapeutic responses produced by DNA-damaging drugs.


Assuntos
Neoplasias/genética , Proteínas Quinases/biossíntese , Proteína Supressora de Tumor p53/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/biossíntese , Catálise/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Dano ao DNA/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular , Células HeLa , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Quinases/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/administração & dosagem
10.
Org Lett ; 16(16): 4158-61, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25061845

RESUMO

Intramolecular dehydro-Diels-Alder (DDA) reactions are performed affording arylnaphthalene or aryldihydronaphthalene lactones selectively as determined by choice of reaction solvent. This constitutes the first report of an entirely selective formation of arylnaphthalene lactones utilizing DDA reactions of styrene-ynes. The synthetic utility of the DDA reaction is demonstrated by the synthesis of taiwanin C, retrohelioxanthin, justicidin B, isojusticidin B, and their dihydronaphthalene derivatives. Computational methods for chemical shift assignment are presented that allow for regioisomeric lignans to be distinguished.


Assuntos
Lactonas/síntese química , Lignanas/síntese química , Naftalenos/síntese química , Reação de Cicloadição , Lactonas/química , Lignanas/química , Estrutura Molecular , Naftalenos/química , Estereoisomerismo , Xantinas/síntese química , Xantinas/química
11.
Org Lett ; 15(11): 2644-7, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-23662902

RESUMO

Syntheses of two 6,12-guaianolide analogs are reported within. The scope of the tandem allylboration/lactonization chemistry is expanded to provide a functionalized allene-yne-containing α-methylene butyrolactone that undergoes a Rh(I)-catalyzed cyclocarbonylation reaction to afford a 5-7-5 ring system. The resulting cycloadducts bear a structural resemblance to other NF-κB inhibitors such as cumambrin A and indeed were shown to inhibit NF-κB signaling and cancer cell growth.


Assuntos
Alcadienos/química , NF-kappa B/antagonistas & inibidores , NF-kappa B/química , Ródio/química , Sesquiterpenos de Guaiano/síntese química , Catálise , Humanos , Estrutura Molecular , NF-kappa B/metabolismo , Oxirredução , Sesquiterpenos de Guaiano/química , Transdução de Sinais , Estereoisomerismo
12.
Org Lett ; 15(11): 2578-81, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-23668292

RESUMO

The synthesis and utility of attachable cyclopenta[b]naphthalene solvatochromic fluorophores related to Prodan are described. Two fluorophores were selected for functionalization and bioconjugation studies. The skeletons were chemically modified to include reactive functional groups and showed minimal alteration of the optical properties when compared to the parent dyes. The functionalized fluorophores were covalently attached to the carboxyl group of a fatty acid, and azido- and thiol-containing amino acids, demonstrating their potential for labeling biomolecules.


Assuntos
Aminoácidos/química , Ciclopentanos/síntese química , Ácidos Graxos/química , Corantes Fluorescentes/química , Naftalenos/química , Solventes/química , Compostos de Sulfidrila/química , Ciclopentanos/química , Estrutura Molecular , Espectrometria de Fluorescência
13.
J Vis Exp ; (74)2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23609566

RESUMO

Functionalized naphthalenes have applications in a variety of research fields ranging from the synthesis of natural or biologically active molecules to the preparation of new organic dyes. Although numerous strategies have been reported to access naphthalene scaffolds, many procedures still present limitations in terms of incorporating functionality, which in turn narrows the range of available substrates. The development of versatile methods for direct access to substituted naphthalenes is therefore highly desirable. The Diels-Alder (DA) cycloaddition reaction is a powerful and attractive method for the formation of saturated and unsaturated ring systems from readily available starting materials. A new microwave-assisted intramolecular dehydrogenative DA reaction of styrenyl derivatives described herein generates a variety of functionalized cyclopenta[b]naphthalenes that could not be prepared using existing synthetic methods. When compared to conventional heating, microwave irradiation accelerates reaction rates, enhances yields, and limits the formation of undesired byproducts. The utility of this protocol is further demonstrated by the conversion of a DA cycloadduct into a novel solvatochromic fluorescent dye via a Buchwald-Hartwig palladium-catalyzed cross-coupling reaction. Fluorescence spectroscopy, as an informative and sensitive analytical technique, plays a key role in research fields including environmental science, medicine, pharmacology, and cellular biology. Access to a variety of new organic fluorophores provided by the microwave-assisted dehydrogenative DA reaction allows for further advancement in these fields.


Assuntos
Corantes/síntese química , Micro-Ondas , Naftalenos/síntese química , Ciclização , Hidrogenação
14.
J Org Chem ; 78(8): 3737-54, 2013 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-23485149

RESUMO

A transfer of chirality in an intramolecular Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) to access tetrahydroazulenones, tetrahydrocyclopenta[c]azepinones and dihydrocyclopenta[c]oxepinones enantioselectively (22-99% ee) is described. The substitution pattern of the allene affected the transfer of chiral information. Complete transfer of chirality was obtained for all trisubstituted allenes, but loss of chiral information was observed for disubstituted allenes. This work constitutes the first demonstration of a transfer of chiral information from an allene to the 5-position of a cyclopentenone using a cyclocarbonylation reaction. The absolute configuration of the corresponding cyclocarbonylation product was also established, something that is rarely done.


Assuntos
Alcadienos/química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/síntese química , Ciclopentanos/química , Ródio/química , Catálise , Ciclização , Estrutura Molecular , Estereoisomerismo
15.
Beilstein J Org Chem ; 8: 1048-58, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23019432

RESUMO

The synthesis of a library of tetrahydro-ß-carboline-containing compounds in milligram quantities is described. Among the unique heterocyclic frameworks are twelve tetrahydroindolizinoindoles, six tetrahydrocyclobutanindoloquinolizinones and three tetrahydrocyclopentenoneindolizinoindolones. These compounds were selected from a virtual combinatorial library of 11,478 compounds. Physical chemical properties were calculated and most of them are in accordance with Lipinski's rules. Virtual docking and ligand-based target evaluations were performed for the ß-carboline library compounds and selected synthetic intermediates to assess the therapeutic potential of these small organic molecules. These compounds have been deposited into the NIH Molecular Repository (MLSMR) and may target proteins such as histone deacetylase 4, endothelial nitric oxide synthase, 5-hydroxytryptamine receptor 6 and mitogen-activated protein kinase 1. These in silico screening results aim to add value to the ß-carboline library of compounds for those interested in probes of these targets.

16.
Org Lett ; 14(17): 4430-3, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22913473

RESUMO

Functionalized naphthalenes are valuable building blocks in many important areas. A microwave-assisted, intramolecular dehydrogenative Diels-Alder reaction of styrenyl derivatives to provide cyclopenta[b]naphthalene substructures not previously accessible using existing synthetic methods is described. The synthetic utility of these uniquely functionalized naphthalenes was demonstrated by a single-step conversion of one of these cycloadducts to a fluorophore bearing a structural resemblance to Prodan.


Assuntos
Corantes Fluorescentes/síntese química , Naftalenos/síntese química , Estirenos/química , Corantes Fluorescentes/química , Micro-Ondas , Estrutura Molecular , Naftalenos/química
17.
J Am Chem Soc ; 134(30): 12418-21, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22793873

RESUMO

The synthesis and photophysical properties of a series of naphthalene-containing solvatochromic fluorophores are described within. These novel fluorophores are prepared using a microwave-assisted dehydrogenative Diels-Alder reaction of styrene, followed by a palladium-catalyzed cross coupling reaction to install an electron donating amine group. The new fluorophores are structurally related to Prodan. Photophysical properties of the new fluorophores were studied and intriguing solvatochromic behavior was observed. For most of these fluorophores, high quantum yields (60-99%) were observed in methylene chloride in addition to large Stokes shifts (95-226 nm) in this same solvent. As the solvent polarity increased, so did the observed Stokes shift with one derivative displaying a Stokes shift of ~300 nm in ethanol. All fluorophore emission maxima, and nearly all absorption maxima were significantly red-shifted when compared to Prodan. Shifting the absorption and emission maxima of a fluorophore into the visible region increases its utility in biological applications. Moreover, the cyclopentane portion of the fluorophore structure provides an attachment point for biomolecules that will minimize disruptions of the photophysical properties.


Assuntos
Corantes Fluorescentes/química , Naftalenos/química , Aminas/química , Reação de Cicloadição , Elétrons , Corantes Fluorescentes/síntese química , Naftalenos/síntese química , Paládio/química , Espectrometria de Fluorescência , Estireno/síntese química , Estireno/química
18.
Org Lett ; 13(23): 6304-7, 2011 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-22070869

RESUMO

Cyclocarbonylation of α-methylene butyrolactone-containing allene-ynes affords 6,12-guaianolide ring systems. Incorporation of the α-methylene butyrolactone early in a synthetic sequence is rare for reactivity reasons; however, this moiety proves to be beneficial to the allenic Pauson-Khand reaction. The three double bonds and the ketone in the resulting 5-7-5 ring system bear significant differences in their reactivity and are ideally positioned for synthetic application to 6,12-guaianolides and analogs.


Assuntos
4-Butirolactona/química , Alcadienos/química , Alquinos/química , Sesquiterpenos de Guaiano/síntese química , 4-Butirolactona/análogos & derivados , Catálise , Técnicas de Química Combinatória , Estrutura Molecular , Sesquiterpenos de Guaiano/química
19.
Beilstein J Org Chem ; 7: 601-5, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21647261

RESUMO

A thermal [2 + 2] cycloaddition reaction of allene-ynes has been used to transform chiral non-racemic allenyl oxindoles into chiral non-racemic spirooxindoles containing an alkylidene cyclobutene moiety. The enantiomeric excesses were determined by chiral lanthanide shift NMR analysis and the transfer of chiral information from the allene to the spirooxindole was found to be greater than 95%.

20.
Proc Natl Acad Sci U S A ; 108(17): 6757-62, 2011 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-21502524

RESUMO

Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.


Assuntos
Desenho de Drogas , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Sondas Moleculares , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Sondas Moleculares/síntese química , Sondas Moleculares/química , Sondas Moleculares/farmacologia , Polyomavirus/fisiologia , Infecções por Polyomavirus/tratamento farmacológico , Infecções por Polyomavirus/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo , Replicação Viral/efeitos dos fármacos
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