- Eco-friendly synthesis and antifungal evaluation of N-substituted benzimidazoles
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Abstract: A convenient synthesis of N-phenacylbenzimidazoles in high yields (90–95%) by the N-alkylation reaction of 1H-benzimidazole with phenacyl bromides is provided. The carbonyl group reduction in the products offered the respective N-(2-aryl-2-hydroxyethyl)benzimidazoles in yields up to 97%. In the optimization of reaction conditions for preparing these N-substituted benzimidazoles (ketones and alcohols), a comparative study between eco-friendly methods (microwave and ultrasound) and conventional heating is described. These antifungal azoles analogs were tested for in vitro antifungal activity against Candida albicans and Cryptococcus neoformans, where the alcohols chlorine substituted (4-Cl and 2,4-Cl2) showed the best activity (MIC50 = 31.2 × 10–6 g/cm3). Graphic abstract: [Figure not available: see fulltext.]
- Butassi, Estefanía,Portilla, Jaime,Vargas-Oviedo, Diana,Zacchino, Susana
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p. 575 - 588
(2020/05/06)
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- ULK1 micromolecule stimulant and application of stimulant in antitumor drug
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The invention relates to an ULK1 micromolecule stimulant and an application of the stimulant in an antitumor drug, which belong to the technical field of antitumor pharmacy. The invention provides a compound taken as the ULK1 micromolecule stimulant. The compound comprises the compound shown in a specification or its pharmaceutically acceptable salt. The compound or its pharmaceutically acceptable salt can be taken as the ULK1 stimulant, has certain antineoplastic activity, and effectively inhibits the growth of the cancer cells. The compound has obvious inhibition effect for a plurality of tumor cells, especially breast cancer cells.
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Paragraph 0096; 0097; 0098; 0100
(2017/07/31)
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- Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo
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UNC-51-like kinase 1 (ULK1) is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. Thus, the activation of ULK1-modulated autophagy could be a promising strategy for breast cancer therapy. In this study, we found that ULK1 was remarkably downregulated in breast cancer tissue samples by The Cancer Genome Atlas (TCGA) analysis and tissue microarray (TMA) analysis, especially in triple negative breast cancer (TNBC). To design a ULK1 agonist, we integrated in silico screening and chemical synthesis to acquire a series of small molecule candidates. After rounds of kinase and anti-proliferative activity screening, we discovered the small molecule, LYN-1604, to be the best candidate for a ULK1 agonist. Additionally, we identified that three amino acid residues (LYS50, LEU53, and TYR89) were key to the activation site of LYN-1604 and ULK1 by site-directed mutagenesis and biochemical assays. Subsequently, we demonstrated that LYN-1604 could induce cell death, associated with autophagy by the ULK complex (ULK1-mATG13-FIP200-ATG101) in MDA-MB-231 cells. To further explore LYN-1604-induced autophagic mechanisms, we found some potential ULK1 interactors, such as ATF3, RAD21, and caspase3, by performing comparative microarray analysis. Intriguingly, we found that LYN-1604 induced cell death involved in ATF3, RAD21, and caspase3, accompanied by autophagy and apoptosis. Moreover, we demonstrated that LYN-1604 has potential for good therapeutic effects on TNBC by targeting ULK1-modulated cell death in vivo; thus making this ULK1 agonist a novel potential small-molecule drug candidate for future TNBC therapy.
- Zhang, Lan,Fu, Leilei,Zhang, Shouyue,Zhang, Jin,Zhao, Yuqian,Zheng, Yaxin,He, Gu,Yang, Shengyong,Ouyang, Liang,Liu, Bo
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p. 2687 - 2701
(2017/04/06)
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- CHEMICAL COMPOUNDS
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Compounds of formula (I):wherein variable groups are as defined within; for use in the inhibition of 11betaHSD1 are described
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- Clean and efficient microwave-solvent-free synthesis of 1-(2′,4′-dichlorophenacyl) azoles
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Microwave induced N-alkylation of several azoles with 2,2′,4′-trichloroacetophenone (TCA) under solvent-free conditions allowed to obtain the corresponding 1-(2′,4′-dichlorophenacyl) azoles with satisfactory to good selectivities and yields. TGA and DSC measurements were achieved for the synthesized compounds and showed a close relationship between the thermal behavior and the reaction temperature under microwave heating. Non-purely thermal microwave effects were evidenced during the alkylation of pyrazole and 1H-indazole under the selected conditions.
- Pérez, Eduardo R.,Loupy, André,Liagre, Marion,De Guzzi Plepis, Ana M.,Cordeiro, Paulo J.
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p. 865 - 870
(2007/10/03)
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