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A theoretical and experimental study to unequivocal structural assignment of tetrahydroquinoline derivatives

da Silva, Bruno Henrique Sacoman Torquato; Marana, Naiara Letícia; Mafud, Ana Carolina; da Silva-Filho, Luiz Carlos
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 1-11
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The tetrahydroquinoline derivatives can be easily synthesized through Povarov reaction and have several important biological activities. This work describes a comparative study for the unequivocal assignment of molecular structure of different tetrahydroquinoline derivatives, through a complete analysis of NMR 1D and 2D NMR spectra (1H, 13C, COSY, HSQC, and HMBC), and the correlation this data with theoretical calculations of energy-minimization and chemical shift (δ), employing the theory level of DFT/B3LYP with set of the cc-pVDZ basis. For these derivatives the experimental analyses and the theoretical model adopted were sufficient to obtain a good description of its structures, and these results can be used to assign the structure of various others tetrahydroquinoline derivatives. © 2013 Springer Science+Business Media New York.

Estudo sobre o uso de compostos de nióbio em reações multicomponentes de aza-Diels-Alder

Silva, Bruno Henrique Sacoman Torquato da
Fonte: Universidade Estadual Paulista (UNESP) Publicador: Universidade Estadual Paulista (UNESP)
Tipo: Dissertação de Mestrado Formato: 337 f. : il.
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Pós-graduação em Ciência e Tecnologia de Materiais - FC; As reações multicomponentes (RMCs) são geralmente definidas como um processo em que três ou mais reagentes combinam-se, em um mesmo pot reacional, para formar um produto que tenha características estruturais de cada reagente utilizado, gerando produtos com uma boa complexidade estrutural em apenas uma etapa. Com base nisto este trabalho tem como objetivo a utilização de diferentes compostos de Nióbio como agente promotor de RMC de aza-Diels-Alder. O pentacloreto de nióbio promove a síntese de diferentes derivados de tetrahidroquinolinas através de reação de derivados de anilina e benzaldeíd e diferentes éteres enólicos cíclicos (di-hidropiano e di-hidrofurano), com baixos tempos reacionais, altos rendimentos e com ótimo excesso diastereoisométricos. Foi estudada também, a utilização do pentaetóxido de nióbio na síntese de derivados de cetoaminas bicíclicas através da RMC entre derivados de anilina, benzaldeído e 2 ciclo-hexenona. A reação foi promovida em moderados tempos reacionais...

N-Aryl-6-methoxy-1,2,3,4-tetrahydroquinolines: a Novel Class of Antitumor Agents Targeting the Colchicine Site on Tubulin

Wang, Xiao-Feng; Wang, Sheng-Biao; Ohkoshi, Emika; Wang, Li-Ting; Hamel, Ernest; Qian, Keduo; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung; Xie, Lan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Structural optimizations of the prior lead 1a led to the discovery of a series of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinoline derivatives as a novel class of tubulin polymerization inhibitors targeted at the colchicine binding site. The most active compound 6d showed extremely high cytotoxicity against a human tumor cell line panel (A549, KB, KBvin, and DU145) with GI50 values ranging from 1.5 to 1.7 nM, significantly more potent than paclitaxel, especially against the drug-resistant KBvin cell line, in the same assays. Analogues 5f, 6b, 6c, and 6e were also quite potent, with a GI50 range of 0.011–0.19 μM. In further studies, active compounds 6b–6e and 5f significantly inhibited tubulin assembly, with IC50 values of 0.92 to 1.0 μM and strongly inhibited colchicine binding to tubulin, with inhibition rates of 75–99% (at 5 μM), comparable with or more potent than combretastatin A-4 (IC50 0.96 μM). Current studies included design, synthesis, and biological evaluations of 24 new compounds (series 3–6). Related SAR analysis, molecular modeling, and evaluation of essential drug-like properties, i.e. water solubility, log P, and in vitro metabolic stability, were also performed.

Microwave-assisted Expeditious and Efficient Synthesis of Cyclopentene Ring-fused Tetrahydroquinoline Derivatives Using Three-component Povarov Reaction

Kulkarni, Abhijit R.; Thakur, Ganesh A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 27/11/2013 EN
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We report here an efficient and expeditious microwave-assisted synthesis of cyclopentadiene ring-fused tetrahydroquinolines using the three-component Povarov reaction catalyzed by indium (III) chloride. This method has an advantage of shorter reaction time (10 – 15 min) with high and reproducible yields (up to 90%) and is suitable for parallel library synthesis. The optimization process is reported and the results from the microwave route are compared with those of the conventional synthetic route. In almost all cases, the microwave acceleration consistently provided improved yields favoring the cis-diastereomer.

Combining structure-based pharmacophore modeling, virtual screening, and in silico ADMET analysis to discover novel tetrahydro-quinoline based pyruvate kinase isozyme M2 activators with antitumor activity

Chen, Can; Wang, Ting; Wu, Fengbo; Huang, Wei; He, Gu; Ouyang, Liang; Xiang, Mingli; Peng, Cheng; Jiang, Qinglin
Fonte: Dove Medical Press Publicador: Dove Medical Press
Tipo: Artigo de Revista Científica
Publicado em 02/09/2014 EN
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Compared with normal differentiated cells, cancer cells upregulate the expression of pyruvate kinase isozyme M2 (PKM2) to support glycolytic intermediates for anabolic processes, including the synthesis of nucleic acids, amino acids, and lipids. In this study, a combination of the structure-based pharmacophore modeling and a hybrid protocol of virtual screening methods comprised of pharmacophore model-based virtual screening, docking-based virtual screening, and in silico ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were used to retrieve novel PKM2 activators from commercially available chemical databases. Tetrahydroquinoline derivatives were identified as potential scaffolds of PKM2 activators. Thus, the hybrid virtual screening approach was applied to screen the focused tetrahydroquinoline derivatives embedded in the ZINC database. Six hit compounds were selected from the final hits and experimental studies were then performed. Compound 8 displayed a potent inhibitory effect on human lung cancer cells. Following treatment with Compound 8, cell viability, apoptosis, and reactive oxygen species (ROS) production were examined in A549 cells. Finally, we evaluated the effects of Compound 8 on mice xenograft tumor models in vivo. These results may provide important information for further research on novel PKM2 activators as antitumor agents.