- Discovery of seneciobipyrrolidine derivatives for the amelioration of glucose homeostasis disorders through 4E-BP1/Akt/AMPK signaling activation
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Modulating the glucose transport in skeletal muscle is a promising strategy for ameliorating glucose homeostasis disorders. However, the complicated mechanisms of glucose transport make it difficult to find compounds therapeutically relevant molecular mechanisms of action, while phenotypic screening is thought to be an alternative approach to mimic the cell state of interest. Here, we report (±)-seneciobipyrrolidine (1a) is first found to enhance glucose uptake in L6 myotubes through phenotype-based screening. Further SAR investigation led to the identfication of compound A27 (EC50 = 2.7 μM). Proteomiic analysis discloses the unique function mechanism of A27 through upregulating the level of the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), subsequently enhancing the Akt and AMPK phosphorylation, thereby promoting the glucose uptake. Chronic oral administration of A27 significantly lowers blood glucose and improves glucose tolerance in db/db mice. This work is new research on seneciobipyrrolidine derivatives, providing a promising avenue for ameliorating glucose homeostasis.
- Che, Jinxin,Ma, Canliang,Lu, Jialiang,Chen, Binhui,Shi, Qiuqiu,Jin, Xinxin,Song, Rui,Xu, Fan,Gan, Lishe,Li, Jingya,Hu, Yongzhou,Dong, Xiaowu
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- Repurposing an Aldolase for the Chemoenzymatic Synthesis of Substituted Quinolines
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Quinoline derivatives are important natural products and pharmaceuticals, but their synthesis can be challenging due to poor yields, harsh reaction conditions, and instability of starting materials. Here we report the chemoenzymatic synthesis of quinaldic acids under mild conditions using an aldolase, trans-o-hydroxybenzylidenepyruvate hydratase-aldolase (NahE, or HBPA). A series of 2-aminobenzaldehydes derived from reduction of the corresponding nitro analogue were reacted with pyruvate in the presence of NahE to give substituted quinolines in up to 93% isolated yield. This reaction differs from the aldol condensation catalyzed by NahE in vivo, instead resembling the heterocycle formation catalyzed by its homologue, dihydrodipicolinate synthase.
- Fansher, Douglas J.,Granger, Richard,Kaur, Satinderpal,Palmer, David R. J.
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p. 6939 - 6943
(2021/06/28)
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- Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors
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In this article, a series of novel quinoline derivatives of ursolic acid (UA) bearing hydrazide, oxadiazole, or thiadiazole moieties were designed, synthesised, and screened for their in vitro antiproliferative activities against three cancer cell lines (MDA-MB-231, HeLa, and SMMC-7721). A number of compounds showed significant activity against at least one cell line. Among them, compound 4d exhibited the most potent activity against three cancer cell lines with IC50 values of 0.12 ± 0.01, 0.08 ± 0.01, and 0.34 ± 0.03 μM, respectively. In particular, compound 4d could induce the apoptosis of HeLa cells, arrest cell cycle at the G0/G1 phase, elevate intracellular reactive oxygen species level, and decrease mitochondrial membrane potential. In addition, compound 4d could significantly inhibit MEK1 kinase activity and impede Ras/Raf/MEK/ERK transduction pathway. Therefore, compound 4d may be a potential anticancer agent and a promising lead worthy of further investigation.
- Jin, Xiao-Yan,Chen, Hao,Li, Dong-Dong,Li, A-Liang,Wang, Wen-Yan,Gu, Wen
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p. 955 - 972
(2019/05/21)
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- Enantioselective synthesis of tunable chiral pyridine-aminophosphine ligands and their applications in asymmetric hydrogenation
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A small library of tunable chiral pyridine-aminophosphine ligands were enantioselectively synthesized based on chiral 2-(pyridin-2-yl)-substituted 1,2,3,4-tetrahydroquinoline scaffolds, which were obtained in high yields and with excellent enantioselectivities via ruthenium-catalyzed asymmetric hydrogenation of 2-(pyridin-2-yl)quinolines. The protocol features a wide substrate scope and mild reaction conditions, enabling scalable synthesis. These chiral P,N ligands were successfully applied in the Ir-catalyzed asymmetric hydrogenation of benchmark olefins and challenging seven-membered cyclic imines including benzazepines and benzodiazepines. Excellent enantio- and diastereoselectivity (up to 99% ee and >20:1 dr), and/or unprecedented chemoselectivity were obtained in the asymmetric hydrogenation of 2,4-diaryl-3H-benzo[b]azepines and 2,4-diaryl-3H-benzo[b][1,4]diazepines.
- Liu, Youran,Chen, Fei,He, Yan-Mei,Li, Chenghao,Fan, Qing-Hua
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p. 5099 - 5105
(2019/05/29)
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- Catalytic Synthesis of Indolines by Hydrogen Atom Transfer to Cobalt(III)–Carbene Radicals
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We report a new method for the synthesis of indolines from o-aminobenzylidine N-tosylhydrazones proceeding through a cobalt(III)–carbene radical intermediate. This methodology employs the use of inexpensive commercially available reagents and allows for the transformation of easily derivatized benzaldehyde-derived precursors to functionalized indoline products. This transformation takes advantage of the known propensity of radicals to undergo rapid intramolecular 1,5-hydrogen atom transfer (1,5-HAT) to form more stabilized radical intermediates. Computational investigations using density functional theory identify remarkably low barriers for 1,5-HAT and subsequent radical rebound displacement, providing support for the proposed mechanism. We explore the effect of a variety of nitrogen substituents, and highlight the importance of adequate resonance stabilization of radical intermediates to the success of the transformation. Furthermore, we evaluate the steric and electronic effects of substituents on the aniline ring. This transformation is the first reported example of the synthesis of nitrogen-containing heterocycles from cobalt(III)–carbene radical precursors.
- Karns, Alexander S.,Goswami, Monalisa,de Bruin, Bas
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supporting information
p. 5253 - 5258
(2017/12/15)
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- Design, synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid
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A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by 1H NMR, 13C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a–d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC50 values of 0.61 ± 0.07, 0.36 ± 0.05, 12.49 ± 0.08 μM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase.
- Gu, Wen,Jin, Xiao-Yan,Li, Dong-Dong,Wang, Shi-Fa,Tao, Xu-Bing,Chen, Hao
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supporting information
p. 4128 - 4132
(2017/08/23)
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- Ursolic acid quinolinyl hydrazide derivative with anti-tumor activity as well as preparation method and application thereof
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The invention discloses an ursolic acid quinolinyl hydrazide derivative with anti-tumor activity as well as a preparation method and application thereof. The invention provides an ursolic acid quinolinyl hydrazide heterocyclic derivative with a structure shown as a general formula I and pharmaceutically acceptable salt thereof: the formula I is shown in the description, wherein I-a: R1 is equal to H and R2 is equal to CH3; I-b: R1 is equal to OMe and R2 is equal to CH3; I-c: R1 is equal to F and R2 is equal to CH3; I-d: R1 is equal to C1 and R2 is equal to CH3; I-e: R1 is equal to H1 and R2 is equal to n-C4H9; I-f: R1 is equal to OMe and R2 is equal to n-C4H9; I-g: R1 is equal to F and R2 is equal to n-C4H9; I-h: R1 is equal to C1 and R2 is equal to n-C4H9. The ursolic acid quinolinyl hydrazide heterocyclic derivative and the pharmaceutically acceptable salt thereof, provided by the invention, have the remarkable anti-tumor activity; a pharmacology experiment shows that the ursolic acid quinolinyl hydrazide derivative disclosed by the invention has a remarkable inhibition effect on human breast cancer cells MDA-MB-231, human cervical cancer cells HeLa and human hepatoma cells SMMC-7721, has low toxicity on human normal epithelial cells QSG-7701 and has a potential of being used for developing anti-tumor drugs.
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Paragraph 0136; 0137; 0139
(2018/01/19)
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- Lewis Acid-Catalyzed C(sp3)–C(sp3) Bond Forming Cyclization Reactions for the Synthesis of Tetrahydroprotoberberine Derivatives
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An efficient Lewis acid-catalyzed C(sp3)–C(sp3) bond forming annulation reaction has been developed. This strategy serves as a new method for the facile synthesis of tetrahydro-5H-isoquinolino[2,1-g][1,6]naphthyridine derivatives. A wide range of 2-methylquinoline-3-carbaldehydes and 1,2,3,4-tetrahydroisoquinolines can be applied for this process to afford structurally diverse tetrahydroprotoberberine derivatives in excellent yields. (Figure presented.).
- Li, Jianjun,Qin, Cong,Yu, Yang,Fan, Huaqiang,Fu, Yiwei,Li, Hao,Wang, Wei
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p. 2191 - 2195
(2017/07/07)
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- Asymmetric synthesis of isoquinolinonaphthyridines catalyzed by a chiral Br?nsted acid
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A catalytic asymmetric method for the synthesis of chiral isoquinolinonaphthyridines has been developed. A chiral disulfonimide catalyzes a redox cyclization reaction between 2-methyl-3-aldehydeazaarenes and 1,2,3,4-tetrahydroisoquinolines to deliver a range of isoquinolinonaphthyridines with good to high yields (up to 91%) and up to 92:8 er.
- Li, Jianjun,Fu, Yiwei,Qin, Cong,Yu, Yang,Li, Hao,Wang, Wei
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p. 6474 - 6477
(2017/08/16)
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- Metal free carboamination of internal alkynes - An easy access to polysubstituted quinolines
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A metal free carboamination of unactivated alkynes towards highly substituted quinolines was realized in the presence of a synergistic Br?nsted acid catalyst system. Supported by mechanistic probes, the reaction proceeds via a highly reactive vinyl cation in a C-C bond formation - Schmidt reaction sequence. The irreversible extrusion of N2, as a powerful driving force, allows for a general conversion of poorly nucleophilic aliphatic alkynes.
- Stopka,Niggemann
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p. 5761 - 5764
(2016/05/19)
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- Synthesis and neuroprotective activity of dictyoquinazol A and analogues
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A flexible and efficient synthesis of the neuroprotective alkaloid, dictyoquinazol A, is reported. Several structural analogues of the target molecule were produced, and the neuroprotective activity of this series of compounds was investigated using three
- Lizarme, Yuvixza,Wangsahardja, Jonatan,Marcolin, Gabriella M.,Morris, Jonathan C.,Jones, Nicole M.,Hunter, Luke
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p. 1480 - 1487
(2016/03/16)
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- Step-economical synthesis of tetrahydroquinolines by asymmetric relay catalytic Friedlaender condensation/transfer hydrogenation
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Two steps in one reaction: The title relay reaction relies on a combination of an achiral Lewis acid and a chiral Bronsted acid (B-H in the scheme). This one-pot method provides access to tetrahydroquinoline derivatives with multiple continuous stereogeni
- Ren, Lei,Lei, Tao,Ye, Jia-Xi,Gong, Liu-Zhu
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supporting information; experimental part
p. 771 - 774
(2012/02/05)
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- S1P MODULATING AGENTS
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Compounds of formula (I) or (II) can modulate the activity of SIP receptors.
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Page/Page column 40
(2012/08/28)
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- Synthesis of quinolinomorphinan derivatives as highly selective δ opioid receptor ligands
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We have reported previously the novel δ opioid agonist KNT-127 which showed high affinity and selectivity for the δ receptor. Moreover, the analgesic effect of subcutaneously administered KNT-127 was more potent than that of a prototypical δ agonist (-)-TAN-67 in the acetic acid writhing test. This study of the structure-activity relationship of KNT-127 derivatives focused on the introduction of substituents onto the 5′-, 6′-, 7′- or 8′-position of the quinoline ring and revealed that many derivatives with 5′- or 8′-substituents showed high affinities and selectivities for the δ receptor. Especially, SYK-153 with an 8′-OH group showed the highest affinity and the most balanced and highest selectivity for the δ receptor among the synthesized compounds.
- Ida, Yoshihiro,Matsubara, Ayaka,Nemoto, Toru,Saito, Manabu,Hirayama, Shigeto,Fujii, Hideaki,Nagase, Hiroshi
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p. 5810 - 5831
(2012/11/06)
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- Synthesis and biological evaluation of novel 7-acyl homocamptothecins as Topoisomerase I inhibitors
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A series of novel 7-acyl derivatives of homocamptothecin (hCPT) were designed and synthesized with the purpose to improve antitumor activity of hCPT, via Minisci free-radical reaction from 10-methoxyhomocamptothecin. All the compounds were evaluated for i
- Liu, Wenfeng,Zhu, Lingjian,Guo, Wei,Zhuang, Chunlin,Zhang, Yongqiang,Sheng, Chunquan,Cheng, Pengfei,Yao, Jianzhong,Wang, Wenya,Dong, Guoqiang,Wang, Shengzheng,Miao, Zhenyuan,Zhang, Wannian
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scheme or table
p. 2408 - 2414
(2011/06/22)
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- Bronsted acid-catalyzed enantioselective Friedlaender condensations: Achiral amine promoter plays crucial role in the stereocontrol
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A highly enantioselective Friedlaender condensation has been established by using chiral Bronsted acids in combination with achiral amines to give quinolines in high yields (up to 99%) and with excellent enantioselectivities (up to 95%).
- Ren, Lei,Lei, Tao,Gong, Liu-Zhu
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supporting information; experimental part
p. 11683 - 11685
(2011/12/02)
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- Excited-state intramolecular proton transfer in 2-(2′- arylsulfonamidophenyl)benzimidazole derivatives: The effect of donor and acceptor substituents
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(Chemical Equation Presented) A series of water-soluble 2-(2′-arylsulfonamidophenyl)benzimidazole derivatives containing electron-donating and accepting groups attached to various positions of the fluorophore π-system has been synthesized and characterize
- Henary, Maged M.,Wu, Yonggang,Cody, John,Sumalekshmy,Li, Jing,Mandal, Subrata,Fahrni, Christoph J.
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p. 4784 - 4797
(2008/02/04)
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- A convenient access to benzo-substituted phthalazines as potential precursors to DNA intercalators
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2-Nitro-5-methoxybenzaldehyde is converted to amines 2 and 7 via two alternative routes. Upon diazotisation and Sandmeyer reaction, halides 4 and 9 are formed, which, through lithiation and formylation lead to the o-phthalaldehyde. Further cyclisation with hydrazine gives the 5-methoxy-substituted phthalazine.
- Tsoungas, Petros G,Searcey, Mark
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p. 6589 - 6592
(2007/10/03)
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