92932-02-0Relevant articles and documents
Design, synthesis, in vitro antiproliferative activity evaluation of 2-alkanoylamidothiophene-3-carboxamide derivatives
Zhang, Jiefeng,Guan, Fengjie,Qiu, Jiakun,Fang, Yanfen,Yu, Lifang,Li, Jingya,Yang, Fan,Zhang, Xiongwen,Li, Jia,Tang, Jie
, p. 2145 - 2165 (2016)
A series of 2-alkanoylamidothiophene-3-carboxamide derivatives were synthesized based on the hit compound 1. The anti-proliferative activity of all the compounds in vitro against MGC-803 (stomach) and HCT-116 (colon) cancer cell lines using SRB assays were tested. Several compounds showed improved anti-proliferative activity against MGC-803 and HCT-116. SAR study revealed that chlorine substituent in the 2-acetylamino part was important for anti-proliferative activity. 5a, 11b, 11c and 11d were the most potent compounds against MGC-803 (IC50s = 2.32-2.95 μM), and 5a and 11c also showed good anti-proliferative activity against HCT-116 cells (IC50s = 3.41-3.75 μM). In addition, the anti-proliferative activity of 11b and 11d could be attributed to the apoptosis in HCT116 cells via caspase 3 activation, confirmed by flow cytometry assay and western blot analysis. Meanwhile, 11b and 11d decreased the mitochondrial membrane potential (MMP) in HCT116 cells.
Design, Synthesis, and Structure-Activity Relationship of N-Aryl- N′-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy
Chen, Zhipeng,Zhang, Lina,Yang, Junjie,Zheng, Lu,Hu, Fanjie,Duan, Siqin,Nandakumar, Kutty Selva,Liu, Shuwen,Yin, Hang,Cheng, Kui
supporting information, p. 7371 - 7389 (2021/06/28)
The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1β from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.
Discovery, structure-activity relationship study and biological evaluation of 2-thioureidothiophene-3-carboxylates as a novel class of C-X-C chemokine receptor 2 (CXCR2) antagonists
Chen, Wenmin,Neamati, Nouri,Xue, Ding
, (2020/08/22)
The C-X-C motif ligand 8 and C-X-C chemokine receptor 2 (CXCL8-CXCR2) axis is involved in pathogenesis of various diseases including inflammation and cancers. Various CXCR2 antagonists are under development for several diseases. Our previous high-throughput cell-based assay specific for CXCR2 has identified a pyrimidine-based compound CX797 acting on CXCR2 down-stream signaling. A lead optimization campaign through scaffold-hopping strategy led to a series of 2-thioureidothiophene-3-carboxylates (TUTP) as novel CXCR2 antagonists. Structure-activity relationship study of TUTPs led to the identification of compound 52 that significantly inhibited CXCR2-mediated β-arrestin recruitment signaling (IC50 = 1.1±0.01 μM) with negligible effect on CXCL8-mediated cAMP signaling and calcium flux. Similar to the known CXCR2 antagonist SB265610, compound 52 inhibited CXCL8-CXCR2 induced phosphorylation of ERK1/2. TUTP compounds also inhibited CXCL8-mediated cell migration and showed synergy with doxorubicin in ovarian cancer cells, thereby supporting TUTPs as promising compounds for cancer treatment.
Identification of small-molecule inhibitors of USP2a
Tomala, Marcin D.,Magiera-Mularz, Katarzyna,Kubica, Katarzyna,Krzanik, Sylwia,Zieba, Bartosz,Musielak, Bogdan,Pustula, Marcin,Popowicz, Grzegorz M.,Sattler, Michael,Dubin, Grzegorz,Skalniak, Lukasz,Holak, Tad A.
supporting information, p. 261 - 267 (2018/03/21)
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a. Iterations of fragment combination and structure-driven design identified two 5-(2-thienyl)-3-isoxazoles as the inhibitors of the USP2a-ubiquitin protein-protein interaction. The affinity of these molecules for the catalytic domain of USP2a parallels their ability to interfere with USP2a binding to ubiquitin in vitro. Altogether, our results establish the 5-(2-thienyl)-3-isoxazole pharmacophore as an attractive starting point for lead optimization.
An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups
Perszyk, Riley,Katzman, Brooke M.,Kusumoto, Hirofumi,Kell, Steven A.,Epplin, Matthew P.,Tahirovic, Yesim A.,Moore, Rhonda L.,Menaldino, David,Burger, Pieter,Liotta, Dennis C.,Traynelis, Stephen F.
, (2018/08/28)
N-methyl-D-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtyp
Synthesis and biological evaluation of 2-acetamidothiophene-3-carboxamide derivatives against Leishmania donovani
Oh, Sangmi,Kwon, Bosung,Kong, Sunju,Yang, Gyongseon,Lee, Nakyung,Han, Dawoon,Goo, Junghyun,Siqueira-Neto, Jair L.,Freitas-Junior, Lucio H.,Liuzzi, Michel,Lee, Jinhwa,Song, Rita
supporting information, p. 142 - 146 (2014/03/21)
A high-throughput (HTS) and high-content screening (HCS) campaign of a commercial library identified 2-acetamidothophen-3-carboxamide as a novel scaffold for developing new anti-leishmanial agents. A series of chemical modifications were performed to study the structure-activity relationship (SAR) and in vitro anti-leishmanial activities were evaluated using biological assays of not only extracellular promastigotes but also intracellular amastigotes. Compound 6a showed promising anti-amastigote activity (EC50 = 6.41 μM) against L. donovani without any cytotoxicity (CC50 > 50 μM) towards human macrophages.
A novel series of positive modulators of the AMPA receptor: Discovery and structure based hit-to-lead studies
Jamieson, Craig,Basten, Stephanie,Campbell, Robert A.,Cumming, Iain A.,Gillen, Kevin J.,Gillespie, Jonathan,Kazemier, Bert,Kiczun, Michael,Lamont, Yvonne,Lyons, Amanda J.,MacLean, John K.F.,Moir, Elizabeth M.,Morrow, John A.,Papakosta, Marianthi,Rankovic, Zoran,Smith, Lynn
scheme or table, p. 5753 - 5756 (2010/12/18)
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Substituted Sulfonamide Compounds
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Page/Page column 38, (2009/01/24)
Substituted sulfonamide compounds corresponding to formula I pharmaceutical compositions comprising them, a process for preparing them, and the use of such compounds to treat or inhibit pain and other disorders or disease states.
PYRAZOLEALKANAMIDE SUBSTITUTED THIOPHENES AS AMPA POTENTIATORS
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Page/Page column 17, (2008/06/13)
The present invention relates to a heterocyclic derivative according to Formula (I) wherein the variables are defined as in the specification, or to a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to a pharmaceuti
