28418-88-4Relevant articles and documents
In pursuit of a selective hepatocellular carcinoma therapeutic agent: Novel thalidomide derivatives with antiproliferative, antimigratory and STAT3 inhibitory properties
Nutt, Michael J.,Yee, Yeung Sing,Buyan, Amanda,Andrewartha, Neil,Corry, Ben,Yeoh, George C.T.,Stewart, Scott G.
, (2021/03/30)
Advanced stage liver cancer is predominantly treated with the multi-kinase inhibitor sorafenib; however, this therapeutic agent lacks selectivity in its cytotoxic actions and is associated with poor survival outcomes. Herein we report the design and preparation of several thalidomide derivatives, including a variety of novel thioether-containing forms that are especially rare in the literature. Importantly, two of the derivatives described are potent antiproliferative agents with dose-dependent selectivity for tumorigenic liver progenitor cells (LPC) growth inhibition (up to 36% increase in doubling time at 10 μM) over non-tumorigenic cells (no effect at 10 μM). Furthermore, these putative anti-liver cancer agents were also found to be potent inhibitors of tumorigenic LPC migration. This report also describes these derivatives’ effects on several key signalling pathways in our novel liver cell lines by immunofluorescence and AlphaLISA assays. Aryl thioether derivative 7f significantly reduced STAT3 phosphorylation (23%) and its nuclear localisation (16%) at 10 μM in tumorigenic LPCs, implicating the IL-6/JAK/STAT3 axis is central in the mode of action of our derivatives.
Preparation method of intermediate containing halogenated benzene ring side-chain flubendiamide structure
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Paragraph 0034; 0036; 0041; 0043; 0047; 0049; 0053; 0055, (2019/01/08)
The invention discloses a preparation method of an intermediate containing a halogenated benzene ring side-chain flubendiamide structure, comprising the following steps: adding 3-iodophthalic acid, toluene and p-methylbenzene sulfonic acid to obtain a 3-iodophthalic anhydride solution; adding triethylamine, cooling, dropwise adding a DMAC solution of 2-methyl-1-methylthiopropylamine to obtain 3-iodine-N-(1,1-dimethyl-2-methylthioethyl)carbamoylbenzoic acid and an isomer solution thereof; adding a dilute sulfuric acid solution, heating, and stirring to obtain 3-iodine-N-(1,1-dimethyl-2-methylthioethyl)carbamoylbenzoic acid and an isomer thereof; and adding a hydrochloric acid solution and heating to 60-80 DEG C and then carrying out thermal insulation for 1-3h, completing the hydrolysis ofthe isomer, cooling to 0-20 DEG C, and carrying out suction filtration to obtain the finished product 3-iodine-N-(1,1-dimethyl-2-methylthioethyl) carbamoylbenzoic acid. By the preparation method of the intermediate containing the halogenated benzene ring side-chain flubendiamide structure, generation of the isomer is reduced and the pollution caused by high consumption of organic solvents is alsoavoided.
OXOINDOLINE DERIVATIVES AS PROTEIN FUNCTION MODULATORS
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Paragraph 0591, (2017/12/16)
The present invention provides chimeric compounds of formula (II) that modulate protein function, to restore protein homeostasis, including cytokine, aiolos, and/or ikaros activity, TNF-alpha activity, CKl-alpha activity and cell-cell adhesion. The invention provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions, including in combination with other cytokine and inflammatory mediators, are provided. Methods of treatment, amelioration, or prevention of protein-mediated diseases, disorders, and conditions, such as cytokine-mediated diseases, disorders, and conditions, including inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant rejection, and cancer, are provided.
Synthesis, insecticidal activities and SAR of novel phthalamides targeting calcium channel
Chen, Youwei,Li, Yuxin,Pan, Li,Liu, Jingbo,Wan, Yingying,Chen, Wei,Xiong, Lixia,Yang, Na,Song, Haibin,Li, Zhengming
, p. 6366 - 6379 (2015/01/09)
In order to find novel and environmental friendly insecticides targeting the ryanodine receptor, three series of novel phthalamides containing heptafluoroisopropyl group, low fluorine atoms group and non-fluorine group were designed and synthesized. 35 novel structures of three series were obtained. Insecticidal activities of title compounds against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of title compounds showed moderate to high activities at the tested concentration. The structure-activity relationship (SAR) was discussed in detail. During synthesizing title compounds B8, C7, D1, D9 and D12, their corresponding positional isomers (B8′, C7′, D1′, D9′ and D12′) were afforded, and their structures were confirmed by 2D NMR. The calcium-imaging technique was also applied to investigate the effects of compounds B2, B10, C4 and C5 on the intracellular calcium ion concentration ([Ca2+]i), which indicated that they released stored calcium ions from endoplasmic reticulum, which denoted that some compounds are potential modulators of the insect ryanodine receptor (RyR).
New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles
Stewart, Scott G.,Braun, Carlos J.,Ng, Sze-Ling,Polomska, Marta E.,Karimi, Mahdad,Abraham, Lawrence J.
supporting information; experimental part, p. 650 - 662 (2010/04/26)
A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFκB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.
JAK INHIBITOR
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Page/Page column 110, (2009/10/21)
A JAK inhibitor comprising, as an active ingredient, a nitrogen-containing heterocyclic compound represented by formula (I) {wherein W represents a nitrogen atom or -CH-; X represents -C (=O) - or -CHR4- (wherein R4 represents a hydrogen atom, or the like); R1 represents the formula described below [wherein Q1 represents-CR8-(wherein R8 represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like); Q2 represents -NR15- (wherein R15 represents a hydrogen atom, substituted or unsubstituted lower alkyl, or the like); and R5 and R6 may be the same or different and each represents a hydrogen atom, halogen, carboxy, substituted or unsubstituted lower alkyl, or the like], or the like; and R2 and R3 may be the same or different and each represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or the like} or a pharmaceutically acceptable salt thereof.
7-[1H-Indol-2-yl]-2,3-dihydro-isoindol-1-ones as dual Aurora-A/VEGF-R2 kinase inhibitors: Design, synthesis, and biological activity
Hughes, Terry V.,Emanuel, Stuart L.,O'Grady, Harold R.,Connolly, Peter J.,Rugg, Catherine,Fuentes-Pesquera, Angel R.,Karnachi, Prabha,Alexander, Richard,Middleton, Steven A.
scheme or table, p. 5130 - 5133 (2009/05/26)
A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed.
INDANONE DERIVATIVES THAT INHIBIT PROLYL HYDROXYLASE
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Page/Page column 32, (2008/12/08)
Compounds of Formula I are useful inhibitors of HIF prolyl hydroxylases. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.
Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling
Stewart, Scott G.,Spagnolo, Daniel,Polomska, Marta E.,Sin, Melvin,Karimi, Mahdad,Abraham, Lawrence J.
, p. 5819 - 5824 (2008/03/13)
A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively. Crown Copyright
SUBSTITUTED DIHYDRO-ISOINDOLONES USEFUL IN TREATING KINASE DISORDERS
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Page/Page column 70, (2008/06/13)
The present invention is directed to novel substituted dihydro-isoindolone compounds of formula (I): and forms thereof, wherein Ring A, X3, R1, R2, R3, R4 and R6 are as herein defined, and their synthesis and use as protein kinase inhibitors and interactions thereof.
