- Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway
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Signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for cancer therapy. In this study, a series of 2-carbonylbenzo[b]thiophene 1,1-dioxide derivatives (CBT) were designed to inhibit the STAT3 SH2 domain phosphorylation site Try 705. We demonstrated that incorporation of basic flexible groups through amide bond linkage to benzo[b]thiophene 1,1-dioxide (BTP) achieved compounds with higher antiproliferative potency than BTP itself. The most potent compound 6o, as indicated from luciferase reporter gene assay, inhibited the STAT3 pathway by decreasing the phosphorylation level of STAT3 Tyr705, while the phosphorylation level of other upstream tyrosine kinases in this pathway was not significantly inhibited. Compound 6o was also shown to trigger ROS generation and accumulation, thus consequently attributed partially to the observed cell apoptosis. This study provided important structural information for the development of inhibitors targeting the STAT3 pathway.
- Ji, Peng,Xu, Xin,Ma, Shuhua,Fan, Junchao,Zhou, Qiang,Mao, Xinliang,Qiao, Chunhua
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- Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broad-spectrum antifungal agents
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To discover antifungal compounds with broad-spectrum and stable metabolism, a series of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. Compounds A30-A34 exhibited excellent broad-spectrum antifungal activity against Candida albicans with MIC values in the range of 0.03–0.5 μg/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25–2 μg/mL. In addition, compounds A31 and A33 showed high metabolic stability in human liver microsomes in vitro, with the half-life of 80.5 min and 69.4 min, respectively. Moreover, compounds A31 and A33 showed weak or almost no inhibitory effect on the CYP3A4 and CYP2D6. The pharmacokinetic evaluation in SD rats showed that compound A31 had suitable pharmacokinetic properties and was worthy of further study.
- Zhao, Liyu,Sun, Yin,Yin, Wenbo,Tian, Linfeng,Sun, Nannan,Zheng, Yang,Zhang, Chu,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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- Amide-Amine Replacement in Indole-2-carboxamides Yields Potent Mycobactericidal Agents with Improved Water Solubility
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Indolecarboxamides are potent but poorly soluble mycobactericidal agents. Here we found that modifying the incipient scaffold by amide-amine substitution and replacing the indole ring with benzothiophene or benzoselenophene led to striking (10-20-fold) im
- Tan, Yu Jia,Li, Ming,Gunawan, Gregory Adrian,Nyantakyi, Samuel Agyei,Dick, Thomas,Go, Mei-Lin,Lam, Yulin
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p. 704 - 712
(2020/11/30)
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- Design, synthesis, and biological evaluation of benzo[b]thiophene 1,1-dioxide derivatives as potent STAT3 inhibitors
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As a member of the signal transducer and activator of transcription (STAT) family, STAT3 plays a critical role in several biological pathways such as cell proliferation, migration, survival, and differentiation. Due to abnormal continuous activation in tumors, inhibition of STAT3 has emerged as an attractive approach for the treatment of various cancer cells. Herein, we report a series of novel STAT3 inhibitors based on benzo[b]thiophene 1,1-dioxide scaffold and evaluated their anticancer potency. Among them, compound 8b exhibited the best activity against cancer cells. Compound 8b induced apoptosis and blocked the cell cycle. Meanwhile, 8b reduced intracellular ROS content and caused the loss of mitochondrial membrane potential. Further research revealed that 8b significantly blocked STAT3 phosphorylation and STAT3-dependent dual-luciferase reporter gene experiments showed that compound 8b has a marked inhibition of STAT3-mediated Firefly luciferase activity. Molecular modeling studies revealed compound 8b occupied the pocket well with the SH2 domain in a favorable conformation.
- Li, Wen-Zhen,Xi, Hui-Zhi,Wang, Yi-Jie,Ma, Hong-Bo,Cheng, Zhi-Qiang,Yang, Yu,Wu, Meng-Ling,Liu, Ting-Mei,Yang, Wen,Wang, Qin,Liao, Meng-Ya,Xia, Yong,Zhang, Yi-Wen
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p. 835 - 849
(2021/09/02)
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- Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors
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STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7a in vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.
- Cai, Guiping,Yu, Wenying,Song, Dongmei,Zhang, Wenda,Guo, Jianpeng,Zhu, Jiawen,Ren, Yuhao,Kong, Lingyi
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p. 236 - 251
(2019/05/02)
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- Antagonizing STAT3 activation with benzo[b]thiophene 1, 1-dioxide based small molecules
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STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[b]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC50range in 0.33–0.75?μM in various cancer cell lines. The overexpressed and IL-6 induced phosphorylation levels of STAT3 were both inhibited by 15 without influencing the phosphorylation levels of the upstream kinases Src and Jak2. 15 also suppressed the expressions of STAT3 downstream gene, Bcl-2. 15 effectively increased the ROS levels of cancer cells, induced cancer cell apoptosis and abolished the colony formation ability of cancer cells without affecting bypass kinase p-Erk. Furthermore, 15 in?vivo induced significant antitumor responses, and exhibited less toxicity than Doxorubicin. Together, this study described a class of new STAT3 inhibitors as antitumor agents.
- Zhang, Wenda,Ma, Ting,Li, Shanshan,Yang, Yanwei,Guo, Jianpeng,Yu, Wenying,Kong, Lingyi
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p. 538 - 550
(2016/10/11)
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- Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
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The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 μM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 μM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 μM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.
- Terzi?, Natasa,Konstantinovi?, Jelena,Tot, Miklo?,Burojevi?, Jovana,Djurkovi?-Djakovi?, Olgica,Srbljanovi?, Jelena,?tajner, Tijana,Verbi?, Tatjana,Zlatovi?, Mario,Machado, Marta,Albuquerque, Inês S.,Prudêncio, Miguel,Sciotti, Richard J.,Pecic, Stevan,D'Alessandro, Sarah,Taramelli, Donatella,?olaja, Bogdan A.
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p. 264 - 281
(2016/01/29)
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- METHOD FOR PROMOTING PLANT GROWTH
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The present invention provides a method for promoting plant growth, which comprises treating a plant with at least one compound selected from a group consisting of a compound represented by the following Formula (1): and an agriculturally acceptable salt thereof, provided that a method for promoting plant growth which comprises treating plants with a compound corresponding to any one of the following (1) to (5) and an agriculturally acceptable salt thereof is excluded: (1) 4-(Trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, (2) 5-(Trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, (3) 6-(Trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, (4) 7-(Trifluoromethyl)benzo[b]thiophene-2-carboxylic acid, and (5) Benzo[b]thiophene-2-carboxylic acid.
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Paragraph 0260; 0261
(2015/11/16)
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- Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents
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The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC50 = 190 nM and with cellular GI50 = 2100 nM, and 6-{2-[4-(2- dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC50 = 9 nM and GI50 = 220 nM.
- Niculescu-Duvaz, Dan,Niculescu-Duvaz, Ion,Suijkerbuijk, Bart M.J.M.,Ménard, Delphine,Zambon, Alfonso,Davies, Lawrence,Pons, Jean-Francois,Whittaker, Steven,Marais, Richard,Springer, Caroline J.
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p. 1284 - 1304
(2013/03/14)
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- 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5 and R6 are as defined herein. The compounds of the present invention have been found to be useful as 17α-hydroxylase/C17,20-lyase inhibitors.
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- ANTI-INFECTIVE PYRIMIDINES AND USES THEREOF
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This invention relates to: (a) compounds and salts thereof that, inter alia, inhibit HCV; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.
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Page/Page column 159
(2009/04/25)
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- COMPOUNDS AND METHODS FOR MODULATING FXR
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Compounds of formula (I) wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.
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Page/Page column 26
(2008/06/13)
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- Amides of acetic and propionic acids
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The invention relates to novel amides of acetic and propionic acids, methods for production and use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning ability and memory.
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- COMPOUNDS AND METHODS FOR MODULATING FXR
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Compounds of formula. wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.
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Page/Page column 36
(2008/06/13)
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- BENZOTHIOPHENE UREA, BENZOFURANE UREA, AND INDOLE UREA, AND USE OF THE SAME AS ALPHA-7 ACHR AGONISTS
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The invention relates to novel benzothiophene urea, benzofurane urea, and indole urea, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration power, learning capacity and/or memory retention.
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Page/Page column 39
(2010/11/30)
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- 2-HETEROARYL CARBOXAMIDES
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The invention relates to the novel 2-heteroaryl carboxamides according to formula (I), wherein R1 represents 1-aza-bicyclo [2.2.2]oct-3-yl, which is optionally replaced via the nitrogen atom by a group selected from the family C1-C4 alkyl, benzyl and oxy, A represents oxygen or sulfur, the ring B represents benzo or pyrido that are optionally replaced by the groups from the family of halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6 alkyl and C1-C6 alkoxy, E represents C=C, aryl and heteroaryl, wherein aryl and heteroaryl may be replaced by groups from the family of halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6 alkoxy and C1-C6 alkyl, and to the solvents, salts or solvents of salts of said compounds. The invention also relates to the use of said compounds in the production of drugs for the treatment and/or the prophylaxis of diseases and for improving perception, power of concentration, learning power and/or retentiveness of memory.
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- Synthesis of Antileukemic Indolylvinyl-1-benzofurans and -benzothiophenes
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2--1-benzofuran and -benzothiophene compounds 6-13 and 18-22 with terminal amidinium or imidazolinium groups were synthesized; in their antileukemic activity in mice they surpass the isosteric 2,2'-vinylenebis(1-benzofuran) and -(benzo-thiophene) compounds.
- Dann, Otto,Char, Helmut,Fleischmann, Paul,Fricke, Helmut
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p. 438 - 455
(2007/10/02)
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