20780-78-3Relevant articles and documents
Synthesis and anti-leukaemic activity of pyrrolo[3,2,1-hi]indole-1,2- diones, pyrrolo[3,2,1-ij]quinoline-1,2-diones and other polycyclic isatin derivatives
Matesic, Lidia,Locke, Julie M.,Vine, Kara L.,Ranson, Marie,Bremner, John B.,Skropeta, Danielle
experimental part, p. 6810 - 6819 (2012/08/28)
To further expand the structure-cytotoxic activity relationships of isatin derivatives and to reduce flexibility in substituent groups at nitrogen, 20 analogues incorporating a ring system between the N1 and C7 atoms of isatin were prepared using a variety of synthetic strategies. This yielded pyrroloindole-, pyrroloquinoline-, pyrroloacridine-, pyrrolophenanthridine- and benzopyrrolophenanthridine-based systems with embedded isatin moieties, the latter possessing a novel carbon skeleton. These compounds were subsequently assessed for their in vitro cytotoxicity against human U937 lymphoma cells, with the brominated pyrroloacridine dione 27 showing the most promising activity (IC50 3.01 μM) after 24 h.
Chemical synthesis, in vitro acetohydroxyacid synthase (AHAS) inhibition, herbicidal activity, and computational studies of isatin derivatives
Wang, Jianguo,Tan, Haizhong,Li, Yonghong,Ma, Yi,Li, Zhengming,Guddat, Luke W.
, p. 9892 - 9900 (2012/01/06)
Acetohydroxyacid synthase (AHAS) catalyzes the first common step in the biosynthesis of the branched-chain amino acids. As a result of its metabolic importance in plants, it is a target for many commercial herbicides. Virtual screening analysis inspired the evaluation of 19 commercially available isatin analogues and 13 newly synthesized isatin derivatives as novel AHAS inhibitors and for their herbicidal activity. The best compound demonstrated 95% inhibition of the activity of Arabidopsis thaliana AHAS at a concentration of 100 mg L-1, whereas the herbicidal activities of three compounds reached 50% inhibition at a concentration of 10 mg L-1 using the rape root growth test. CoMFA contour models were established to understand the structure-activity relationships for this class of AHAS inhibitor. The compounds were docked to the active site cavity of A. thaliana AHAS using FlexX, and the dominant binding mode was consistent with frontier molecular orbital from DFT calculations. This is the first comprehensive study of isatin derivatives as AHAS inhibitors and provides a valuable starting point for the design of new herbicides.
7-SUBSTITUTED INDIRUBIN-3'OXIMES AND THEIR APPLICATIONS
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Page/Page column 5, (2011/01/05)
The invention relates to new 3′-, 7-substituted-indirubins of formula (I) wherein R represents N—OH, N—O-alkyl or N—O—CO-alkyl, NO—(Ra)n1-Het, N—O—(Y)n1—NRaRb, N—O—CO—N(RbRc), ra
DIHYDROOROTATE DEHYDROGENASE INHIBITORS
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Page/Page column 114, (2010/11/03)
The invention relates to compounds of formula (I) wherein R1, R2, X1, X2, Y, Ra, Rb, Q have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis and also in the treatment of cancer disorders.
Methods and Compositions for Selectin Inhibition
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Page/Page column 16, (2008/12/04)
The present teachings relate to novel compounds of formula I: wherein the constituent variables are as defined herein. Compounds of the present teachings can act as antagonists of the mammalian adhesion proteins known as selecting. Methods for treating or preventing selectin-mediated disorders are provided, which include administration of these compounds in a therapeutically effective amount.
Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists
Kaila, Neelu,Janz, Kristin,DeBernardo, Silvano,Bedard, Patricia W.,Camphausen, Raymond T.,Tam, Steve,Tsao, Desirée H.H.,Keith Jr., James C.,Nickerson-Nutter, Cheryl,Shilling, Adam,Young-Sciame, Ruth,Wang, Qin
, p. 21 - 39 (2008/02/02)
Leukocyte recruitment of sites of inflammation and tissue injury involves leukocyte rolling along the endothelial wall, followed by firm adherence of the leukocyte, and finally transmigration of the leukocyte across cell junctions into the underlying tissue. The initial rolling step is mediated by the interaction of leukocyte glycoproteins containing active moieties such as sialyl Lewisx (sLex) with P-selectin expressed on endothelial cells. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of inflammatory diseases such as arthritis. High-throughput screening of the Wyeth chemical library identified the quinoline salicylic acid class of compounds (1) as antagonists of P-selectin, with potency in in vitro and cell-based assays far superior to that of sLex. Through iterative medicinal chemistry, we identified analogues with improved P-selectin activity, decreased inhibition of dihydrooratate dehydrogenase, and acceptable CYP profiles. Lead compound 36 was efficacious in the rat AIA model of rheumatoid arthritis.
2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H] quinoline-4-carboxylic acid (PSI-697): Identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists
Kaila, Neelu,Janz, Kristin,Huang, Adrian,Moretto, Alessandro,DeBernardo, Silvano,Bedard, Patricia W.,Tam, Steve,Clerin, Valerie,Keith Jr., James C.,Tsao, Desirée H.H.,Sushkova, Natalia,Shaw, Gray D.,Camphausen, Raymond T.,Schaub, Robert G.,Wang, Qin
, p. 40 - 64 (2007/10/03)
P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
3′-substituted 7-halogenoindirubins, a new class of cell death inducing agents
Ferandin, Yoan,Bettayeb, Karima,Kritsanida, Marina,Lozach, Olivier,Polychronopoulos, Panagiotis,Magiatis, Prokopios,Skaltsounis, Alexios-Leandros,Meijer, Laurent
, p. 4638 - 4649 (2007/10/03)
Indirubins are kinase inhibitory bis-indoles that can be generated from various plant, mollusk, mammalian, and bacterial sources or chemically synthesized. We here report on the synthesis and biological evaluation of 3′-substituted 7-halogenoindirubins. M
Methods and compositions for selectin inhibition
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Page/Page column 12-13, (2008/06/13)
The present invention relates to the field of anti-inflammatory substances, and more particularly to novel compounds that act as antagonists of the mammalian adhesion proteins known as selectins. In some embodiments, methods for treating selectin mediated
Total synthesis of TMC-95A and -B via a new reaction leading to Z-enamides. Some preliminary findings as to SAR
Lin, Songnian,Yang, Zhi-Qiang,Kwok, Benjamin H. B.,Koldobskiy, Michael,Crews, Craig M.,Danishefsky, Samuel J.
, p. 6347 - 6355 (2007/10/03)
A full account of the total syntheses of proteasome inhibitors TMC-95A and -B is provided. A key feature of the syntheses involved installation of a cis-propenylamide moiety by a thermal rearrangement of an α-silylallyl amide. The scope and mechanism of the enamide-forming reaction are discussed. Also provided are some preliminary results from SAR studies. It was found that simplified analogues can retain the full potency of proteasome inhibition.
