- Discovery of novel tubulin inhibitors targeting the colchicine binding site via virtual screening, structural optimization and antitumor evaluation
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The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance. For identifying novel tubulin inhibitors, structure-based virtual screening was applied to identify hit 9 which displayed moderate tubulin polymerization inhibition and broad-spectrum in vitro antitumor activity. Structural optimization was performed, and biological assay revealed analog E27 displayed the best antitumor activity with IC50 values ranging from 7.81 μM to 10.36 μM, and improved tubulin polymerization inhibitory activity (IC50 = 16.1 μM). It significantly inhibited cancer cell migration and invasion, induced cell apoptosis and arrested the cell cycle at G2/M phase. Moreover, the apoptotic effect of E27 is related to the increased ROS level, the decrease of MMP, and the abnormal expression of apoptosis-related proteins. Taken together, these results suggested E27 was a promising lead compound for discovering novel tubulin-targeted antitumor agents.
- Liu, Wei,Jia, Hairui,Guan, Minghao,Cui, Minxuan,Lan, Zhuxuan,He, Youyou,Guo, Zhongjie,Jiang, Ru,Dong, Guoqiang,Wang, Shengzheng
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- Direct C-C Bond Cleavage of 1,3-Dicarbonyl Compounds as a Single-Carbon Synthon: Synthesis of 2-Aryl-4-quinolinecarboxylates
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A novel [2 + 1 + 3] cyclization reaction for the synthesis of 2-aryl-4-quinolinecarboxylates from aryl methyl ketones, arylamines, and 1,3-dicarbonyl compounds has been established. This metal-free process achieved the C-C bond cleavage of 1,3-dicarbonyl compounds directly as a single-carbon synthon. The reaction is highly efficient and has good substrate compatibility while operating under mild conditions. This method has good practicability and successfully realized the synthesis of bioactive molecules.
- Zhou, You,Zhao, Peng,Wang, Li-Sheng,Yu, Xiao-Xiao,Huang, Chun,Wu, Yan-Dong,Wu, An-Xin
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p. 6461 - 6465
(2021/08/23)
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- A green synthesis of quinoline-4-carboxylic derivatives using p-toluenesulfonic acid as an efficient organocatalyst under microwave irradiation and their docking, molecular dynamics, ADME-Tox and biological evaluation
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P-Toluenesulfonic acid, being an efficient, nonhazardous, and fast accessible organocatalyst, was used for the preparation of quinoline-4-carboxylic acid derivatives via a one-pot three-component reaction of aromatic benzaldehyde, substituted aniline, and pyruvic acid under microwave irradiation. After completion of the reaction, the pure products were isolated by column chromatography. Here, to achieve the desired synthesis, various catalytic and solvent conditions were applied to perform a comparison study. We are using higher yield, simple work-up process, avoiding the use of hazardous organic solvents, short reaction time and higher advantages of the present protocol in the study. Biological activities of synthesized compounds were tested against various antibacterial, antifungal, antimalarial, and antituberculosis strains. Compounds 4a and 4c (MIC 50 μg/mL) and compounds 4d and 4n (MIC 62.5 μg/mL) were found active against the Escherichia coli strain, compounds 4c and 4p (MIC 25 μg/mL) were found active against the Staphylococcus aureus strain, and compounds 4c and 4d were found active against the Plasmodium falciparum strain. Molecular docking revealed that ligands and proteins fitted exactly in the binding pocket and had significant correlation with the biological activity. We have also tested molecular dynamics and ADME-Tox parameters for the synthesized compounds.
- Patel, Dhaval B.,Patel, Hitesh D.,Rajani, Dhanji P.,Rajani, Smita D.
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- Synthesis and evaluation of antibacterial and antioxidant activity of novel 2-phenyl-quinoline analogs derivatized at position 4 with aromatically substituted 4H-1,2,4-triazoles
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A set of novel quinolone–triazole conjugates (12–31) were synthesized in three steps in good yields starting from 2-phenylquinoline-4-carboxylic acid. All the intermediates, as well as the final 1,2,4-triazolyl quinolines were fully characterized by their detailed spectral analysis utilizing different techniques such as IR, 1H NMR, 13C NMR, and finally mass spectrometry. All the synthesized compounds were evaluated in vitro for their potential antibacterial activity and their preliminary safety profile was assessed through cytotoxicity assay. Additionally, six selected conjugates were evaluated for their antioxidative properties on the basis of density functional theory calculations, using radical scavenging assay (DPPH) and cellular antioxidant assay. The reported results encourage further investigation of selected compounds and are shading light on their potential pharmacological use.
- Verbanac, Donatella,Malik, Ritu,Chand, Mahesh,Kushwaha, Khushbu,Vashist, Monika,Matija?i?, Mario,Stepani?, Vi?nja,Peri?, Mihaela,Paljetak, Hana ?ip?i?,Saso, Luciano,Jain, Subhash C.
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p. 104 - 110
(2016/12/14)
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- Design, synthesis and evaluation of quinoline-based small molecule inhibitor of stat3
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As STAT3 has been validated as an anticancer target, its inhibitors have been shown to possess therapeutic promise for the treatment of human cancers. To identify novel and selective STAT3 inhibitors, a virtual screening based on the STAT3 SH2 domain was performed and a small molecule, 2-phenylquinoline-4- carboxylic acid (5a), with an inhibition constant Ki value of 17.53 iM to STAT3 was discovered. On this basis, the derivatives of 5a including esters, amides and dimers were synthesized. The bioactivity and inhibitory selectivity of the derivatives were assayed using human breast cancer cell lines, MDA-MB-468 and MCF-7. Among the derivatives, 5c and 9b showed the most potent inhibitory activity with a good selectivity, and also inhibited STAT3 protein level of MDA-MB-468 cells. The results demonstrated a successful application of virtual screening for lead discovery. Compound 9b might be an effective STAT3 inhibitor lead for the further development of antitumor agents.
- Shi, Zhi-Bing,Zhang, Lei,Bin, Zheng-Yang,Cao, Xiang-Rong,Gong, Zhu-Nan,Li, Jian-Xin
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p. 420 - 426
(2013/07/26)
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- Synthesis of some 2-aryl- and 2,3-diaryl-quinolin-4-carboxylic acid derivatives
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Eighteen 2-aryl- and 2,3-diaryl-quinolin-4-carboxlic acid derivatives were synthesized. Basically, the synthetic design of these compounds arose from the appropriate disconnections of the target compounds, which revealed pyruvic acid, aromatic amine, and benzaldehyde or phenyl pyruvic acid, aromatic amine, and benzaldehyde as possible logical precursors for 2-aryl- and 2,3-aryl-quinolin-4- carboxylic acids respectively. The purity and identities of the synthesized compounds were elucidated through chromatographic and spectroscopic techniques (ultraviolet, infrared, mass, 1H NMR, and 13C NMR). The prepared derivatives were screened for their antibacterial activity against the standard bacterial organisms B. subtilis, S. aureus, E. coli, and P. vulgaris. 2,3-Diphenyl-6-sulfanilamido-quinolin-4-carboxylic acid showed the highest activity against the four tested organisms.
- Saeed,Elhadi
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experimental part
p. 1435 - 1443
(2011/06/20)
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- One-pot synthesis of quinoline-4-carboxylic acid derivatives in water: Ytterbium perfluorooctanoate catalyzed Doebner reaction
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Ytterbium perfluorooctanoate [Yb(PFO)3] has been proved to be an efficient catalyst for Doebner reaction of pyruvic acid, aldehydes and amines under mild conditions in water to afford quinoline-4-caboxylic acid derivatives with three component one-pot method in good yields. The process is operationally simple and environmentally benign and the catalyst has readily been recycled for several times with consistent activity. Furthermore, a plausible mechanism for this transformation is also presented.
- Wang, Li-Min,Hu, Liang,Chen, Hong-Juan,Sui, Yuan-Yuan,Shen, Wei
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experimental part
p. 406 - 409
(2009/12/03)
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- ACRIDINE AND QUINOLINE SIRTUIN MODULATORS
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Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, chemo therapeutic induced neuropathy, neuropathy associated with an ischemic event, polyglutamine diseases, ocular diseases and/or disorders, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
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Page/Page column 34; 147-148
(2008/06/13)
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- Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase
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A series of 2-phenyl quinoline-4-carboxylic acid derivatives related to brequinar, an inhibitor of human dihydroorotate dehydrogenase (DHODH), has been prepared and evaluated as inhibitors of DHODH from the malaria parasite Plasmodium falciparum. Brequinar was essentially inactive against PfDHODH (IC50 880 μM) whereas several members of the series inhibited PfDHODH. Unexpectedly, replacement of the carboxylic acid required for brequinar to inhibit hDHODH was not essential in the diisopropylamides that inhibited PfDHODH.
- Boa, Andrew N.,Canavan, Shane P.,Hirst, Paul R.,Ramsey, Christopher,Stead, Andrew M.W.,McConkey, Glenn A.
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p. 1945 - 1967
(2007/10/03)
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