RESUMO
In the title mol-ecule, C20H17Cl2NO2, the pyrrole moiety makes dihedral angles of 63.42â (11) and 70.43â (12)° with the chlorobenzene rings. The eth-oxy-carbonyl unit is present in a synperiplanar conformation with respect to the pyrrole ring, as indicated by the dihedral angle of 14.5â (3)°. In the crystal, mol-ecules are linked into chains parallel to the a-axis direction by weak C-Hâ¯O hydrogen bonds.
RESUMO
In the mol-ecule of the title compound, C21H14N2O3, the quinazoline ring system [maximum deviation = 0.076â (1)â Å] makes dihedral angles of 40.57â (9) and 42.31â (11)°, respectively, with the phenyl and 1,3-benzodioxole rings. The dihedral angle between the phenyl ring and the 1,3-benzodioxole ring is 4.34â (10)°. In the crystal, C-Hâ¯O hydrogen bonds link the mol-ecules into infinite zigzag chains extending along [100].
RESUMO
Aurora kinases are essential for chromosomal segregation and cell division and thereby important for maintaining the proper genomic integrity. There are three classes of aurora kinases in humans: A, B, and C. Aurora kinase A is frequently overexpressed in various cancers. The link of the overexpression and tumorigenesis is yet to be understood. By employing virtual screening, we have found that anacardic acid, a pentadecane aliphatic chain containing hydroxylcarboxylic acid, from cashew nut shell liquid could be docked in Aurora kinases A and B. Remarkably, we found that anacardic acid could potently activate the Aurora kinase A mediated phosphorylation of histone H3, but at a similar concentration the activity of aurora kinase B remained unaffected in vitro. Mechanistically, anacardic acid induces the structural changes and also the autophosphorylation of the aurora kinase A to enhance the enzyme activity. This data thus indicate anacardic acid as the first small-molecule activator of Aurora kinase, which could be highly useful for probing the function of hyperactive (overexpressed) Aurora kinase A.
Assuntos
Ácidos Anacárdicos/química , Ativadores de Enzimas/química , Proteínas Serina-Treonina Quinases/química , Ácidos Anacárdicos/isolamento & purificação , Anacardium , Aurora Quinase A , Aurora Quinase B , Aurora Quinases , Linhagem Celular , Clonagem Molecular , Cristalografia por Raios X , Ativadores de Enzimas/isolamento & purificação , Histonas/química , Humanos , Cinética , Modelos Moleculares , Estrutura Molecular , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Espectrometria de FluorescênciaRESUMO
Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-molecule inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells. We show that the specific inhibitor selectively represses the p300-mediated acetylation of p53 in vivo. Furthermore, inhibition of p300-HAT down regulates several genes but significantly a few important genes are also upregulated. Remarkably, these inhibitors were found to be nontoxic to T cells, inhibit histone acetylation of HIV infected cells, and consequently inhibit the multiplication of HIV.
Assuntos
Fármacos Anti-HIV , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores Enzimáticos , Expressão Gênica/efeitos dos fármacos , HIV-1 , Histona Acetiltransferases/antagonistas & inibidores , Terpenos , Fatores de Transcrição/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Acetilação , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Proteínas de Ciclo Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Cromatina/genética , Regulação para Baixo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/fisiologia , Células HeLa , Histona Acetiltransferases/genética , Histonas/genética , Humanos , Modelos Moleculares , Estrutura Molecular , Linfócitos T/virologia , Terpenos/síntese química , Terpenos/química , Terpenos/farmacologia , Fatores de Transcrição/genética , Transcrição Gênica , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , Fatores de Transcrição de p300-CBPRESUMO
Reversible acetylation of nucleosomal histones and nonhistone proteins play pivotal roles in the regulation of all the DNA templated phenomenon. Dysfunction of the enzymes involved in the acetylation/deacetylation leads to several diseases. Therefore, these enzymes are the targets for new generation therapeutics. Here, we report the synthesis of trifluoromethyl phenyl benzamides and their effect on histone acetyltransferase (HAT) activity of p300. One of these benzamides, CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), was discovered as a potent activator of the p300 HAT activity. We have found that pentadecyl hydrocarbon chain of CTPB is required to activate the HAT only under certain context. Furthermore, our results show that the relative position of -CF3 and -Cl in CTB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide) is also very critical for the activation. Surface-enhanced Raman spectroscopy (SERS) of p300 and the HAT activator complexes evidently suggest that the activation of HAT activity is achieved by the alteration of p300 structure. Therefore, apart from elucidating the chemical basis for small molecule mediated activation of p300, this report also describes, for the first time, Raman spectroscopic analysis of the complexes of histone-modifying enzymes and their modulators, which may be highly useful for therapeutic applications.
Assuntos
Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Histona Acetiltransferases/química , Histona Acetiltransferases/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Ácidos Anacárdicos/química , Benzamidas/química , Benzamidas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Células HeLa , Humanos , Hidrocarbonetos/química , Cinética , Estrutura Molecular , Ácido Salicílico/química , Análise Espectral Raman , Fatores de Transcrição de p300-CBPRESUMO
The synthesis of adducts of arylamines with adenosine are reported.
Assuntos
Adenosina/análogos & derivados , Aminas/química , Adutos de DNA/química , Adenosina/síntese química , Adenosina/química , Aminas/síntese química , Compostos de Anilina/química , Adutos de DNA/síntese química , Espectroscopia de Ressonância Magnética , Metilação , Espectrofotometria InfravermelhoRESUMO
A one-pot, three-component, microwave irradiated and conventional solution-phase synthesis of bioactive venlafaxine analogs such as 2,3-disubstituted-1,3-thiazolidin-4-ones 3a-j under mild conditions and their characterization are reported. The novel thiazolidin-4-ones, 3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)-2-phenyl-thiazolidin-4-one 3a, 2-(2,6-difluorophenyl)-3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)thiazolidin-4-one 3c, and 2-(furan-2-yl)-3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)thiazolidin-4-one 3i, were characterized by the single crystal X-ray diffraction method. The cyclohexane ring of all the three molecules is in chair conformation. All the synthesized compounds were screened for their efficacy as antimicrobials in vitro by the disk diffusion and microdilution method against pathogenic strains such as Bacillus subtilis, Escherichia coli, Pseudomonas fluorescens, Xanthomonas campestris pvs, Xanthomonas oryzae, Aspergillus niger, Aspergillus flavus, Fusarium oxysporum, Trichoderma species, and Fusarium monaliforme species. Among these compounds 3c, 3j, 3g, 3d, and 3e showed potent antimicrobial activity, when compared to standard drugs.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Cicloexanóis/síntese química , Cicloexanóis/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Antibacterianos/química , Cristalografia por Raios X , Cicloexanóis/química , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Cloridrato de VenlafaxinaRESUMO
The synthesis of novel imidazolyl substituted delta2-isoxazoline libraries are currently of high interest. We report here in the full details of a study leading to the synthesis and antifungal activities of 3-(-2-butyl-4-chloro-1H-imidazolyl)-substituted delta2-isoxazolines. The solution phase synthesis of the title compounds was accomplished via 1,3-dipolar cycloaddition of in situ generated nitryl oxides from aldoximes with mono substituted alkenes to obtain the compound libraries contain an imidazole functionality in addition to the isoxazoline rings. The newly synthesized compounds when tested in vitro in solid agar culture exerted a potent antifungal activity against Aspergillus flavus, Fusarium moniliforme and Botrydiplodia theobromae also MIC values were determined. The title 5-substituted-3-imidazolyl-delta2-isoxazoline compounds represent a novel class of potent antifungal agents.