- Diversity-oriented generation and biological evaluation of new chemical scaffolds bearing a 2,2-dimethyl-2H-chromene unit: Discovery of novel potent ANO1 inhibitors
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Chemical territory bearing a 2,2-dimethyl-2H-chromene motif was expanded by utilizing an o-hydroxy aldehyde group of 5-hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde as a synthetic handle to install distinctive morphology and functionality of each scaffold. Cell based assays and in silico docking analysis led us to discover that these new compounds exhibit inhibitory effect on anoctamin1 (ANO1). ANO1 is amplified and highly expressed in various carcinomas including prostate cancer, esophageal cancer, breast cancer, and pancreatic cancer. Biological assays revealed that (E)-1-(7,7-dimethyl-7H-furo[2,3-f]chromen-2-yl)-3-(1H-pyrrol-2-yl)prop-2-en-1-one (3n, Ani-FCC) is a novel, potent and selective ANO1 inhibitor with an IC50 value of 1.23 μM. 3n showed 144 times stronger activity on ANO1 inhibition than ANO2 inhibition and did not alter the chloride channel activity of CFTR and the intracellular calcium signaling. Notably, 3n strongly decreased cell viability of PC-3 and FaDu cells expressing high levels of ANO1 with a decrease in ANO1 protein levels. In addition, 3n significantly enhanced apoptosis via activation of caspase 3 and cleavage of PARP in PC-3 and FaDu cells. This study shows that a novel ANO1 inhibitor, 3n, can be a potential candidate for the treatment of cancers overexpressing ANO1, such as prostate cancer and esophageal cancer.
- Choi, Jiwon,Han, Gyoonhee,Kim, Ikyon,Kim, Tae Gun,Lee, Jeong Hwa,Namkung, Wan,Park, So-hyeon,Seo, Yohan
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Read Online
- An unexpected pericyclic reaction between propiolic ester and a 2-vinyl benzofuran
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A 2:1 adduct of hitherto unknown structure results from heating methyl propiolate 1 and 2-isopropenyl-6-methoxybenzofuran 2. We describe a series of chemical and NMR spectroscopic studies which elucidate the structure of this material, and propose a mechanism for its formation.
- De Capite,Puar,Burke,Scannell,Stevenson
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Read Online
- Synthesis and Anti-Cholinesterase Activity of Novel Glycosyl Benzofuranylthiazole Derivatives
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Abstract: A new series of glycosyl benzofuranylthiazole derivatives were designed, synthesized, characterized, and evaluated as potential candidates to treat Alzheimer’s disease. The compounds have been synthesized by the cyclocondensation of glycosyl thiourea with a variety of 2-(bromoacetyl)benzofurans. The reaction conditions have been optimized, and good yields (79–95%) have been obtained. The synthesized compounds showed different degrees of cholinesterase inhibitory activity.
- Cao, L.,Cao, Zh.,Chen, Ch.,Jiang, K.,Liu, Sh.,Liu, W.,Lu, X.,Shao, Zh.,Shi, D.,Su, Z.,Wang, L.,Wang, Y.,Wu, Y.
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p. 1513 - 1518
(2021/10/26)
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- Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy
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In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.
- Miller, Michael M.,Banville, Jacques,Friends, Todd J.,Gagnon, Mark,Hangeland, Jon J.,Lavallée, Jean-Fran?ois,Martel, Alain,O'Grady, Harold,Rémillard, Roger,Ruediger, Edward,Tremblay, Fran?ois,Posy, Shana L.,Allegretto, Nick J.,Guarino, Victor R.,Harden, David G.,Harper, Timothy W.,Hartl, Karen,Josephs, Jonathan,Malmstrom, Sarah,Watson, Carol,Yang, Yanou,Zhang, Ge,Wong, Pancras,Yang, Jing,Bouvier, Michel,Seiffert, Dietmar A.,Wexler, Ruth R.,Lawrence, R. Michael,Priestley, E. Scott,Marinier, Anne
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p. 7400 - 7416
(2019/08/26)
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- Synthesis and bioactivity of novel C2-glycosyl benzofuranylthiazoles derivatives as acetylcholinesterase inhibitors
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A new series of C2-glycosyl benzofuranylthiazole derivatives was synthesised by the further cyclization of glycosyl thiourea and 2-(bromoacetyl)-benzofuran via Hantzsch’s method. The corresponding 2-(bromoacetyl)-benzofuran derivatives were obtained by the reaction from various salicylaldehydes, and the glycosyl thiourea was prepared through a series of steps from D-Glucosamine. The acetylcholinesterase-inhibitory activities of the products were tested by Ellman’s method. The most active compounds were subsequently evaluated for the 50% inhibitory concentration values. N-(1,3,4,6-tetra-O-benzyl-2-deoxy-β-D-glucopyranosyl)-4-(5-methoxy-benzofuran-2-yl)-1,3-thiazole-2-amine possessed the best acetylcholinesterase-inhibition activity with a 50% inhibitory concentration of 2.03 ± 0.26 μM.
- Wang, Lei,Wu, Yu-Ran,Ren, Shu-Ting,Yin, Long,Wang, You-Xian,Liu, Shu-Hao,Liu, Wei-Wei,Shi, Da-Hua,Cao, Zhi-Ling,Sun, Hui-Min
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p. 257 - 261
(2019/09/03)
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- TBAI/TBHP mediated oxidative cross coupling of ketones with phenols and carboxylic acids: Direct access to benzofurans
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TBAI/TBHP mediated oxidative cross coupling of phenols and carboxylic acids with ketones has been reported under metal-free, base free, solvent free conditions enabling environmentally benign synthesis of aryloxyketones, acyloxy ketones and benzofurans. Phenoxyketones and acyloxylcarbonyl compounds were synthesized in good to high yields, where as benzofurans were synthesized in moderate yields. This method is operationally simple, works under mild conditions, using commercially available as well as inexpensive TBAI and an oxidant TBHP.
- Santhosh Kumar,Ravikumar,Chinna Ashalu,Rajender Reddy
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supporting information
p. 33 - 37
(2017/12/11)
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- 1,3-disubstituted ketene compound and application thereof
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The invention relates to a 1,3-disubstituted ketene compound with a structure as shown in a formula (I) and application thereof. The compound mainly activates a PPAR (Peroxisome Proliferators-Activated Receptor) alpha, and also has excitation activity for PPPA delta and PPPA gamma. The 1,3-disubstituted ketene compound can be used for treating various diseases related to the PPAR regulation abnormality, such as NASH (nonalcoholic steatohepatitis), and particularly treating nonalcoholic hepatitis, also has potentials for treating diabetes, obesity, fibrotic diseases, cardiovascular diseases (comprising a heart failure, atherosclerosis and the like), kidney diseases (comprising chronic nephrosis, a kidney failure and the like), brain degenerative diseases (comprising the alzheimer disease and the like) and the like, and has higher application value. The formula is shown in the description.
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Paragraph 0222; 0223
(2018/11/03)
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- Novel bioactivation pathway of benzbromarone mediated by cytochrome P450
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Benzbromarone (BBR) is a hepatotoxic drug, but the detailed mechanism of its toxicity remains unknown. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (2-ethyl-3-(3-bromo-4,5-dihydroxybenzoyl) benzofuran; CAT) as novel metabolites of BBR in rat and human liver microsomal systems by comparison with chemically synthesized authentic compounds, and we also elucidated that DBH is formed by cytochrome P450 2C9 and that CAT is formed mainly by CYP1A1, 2D6, 2E1, and 3A4. Furthermore, CAT, DBH, and the oxidized form of DBH are highly cytotoxic in HepG2 compared with BBR. Taken together, our data demonstrate that DBH, a novel reactive metabolite, may be relevant to BBR-induced hepatotoxicity.
- Kitagawara, Yumina,Ohe, Tomoyuki,Tachibana, Kumiko,Takahashi, Kyoko,Nakamura, Shigeo,Mashino, Tadahiko
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supporting information
p. 1303 - 1306
(2015/09/07)
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- NEW ARYLALKENYLPROPARGYLAMINE DERIVATIVES EXHIBITING NEUROPROTECTIVE ACTION FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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The invention relates to novel arylalkenylpropargylamine derivatives of general formula (I) or enantiomers or diastereomers thereof or salts, optionally pharmaceutically acceptable salts, or solvates of any of these. The compounds can be used in treating or preventing a disease or condition in a mammal related to monoamine oxidase dysfunction, especially in neurodegenerative diseases, e.g. Parkinson's disease, Alzheimer's disease or Huntington's disease.
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Page/Page column 27; 43
(2015/06/25)
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- Efficient synthetic approach to substituted benzo[b]furans and benzo[b]thiophenes by iodine-promoted cyclization of enaminones
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An efficient synthetic approach to the substituted benzo[b]furan and benzo[b]thiophene scaffolds by iodine-mediated cyclization of the corresponding enaminones is described. This protocol was applied to a large series of these latter precursors to afford the respective benzoheterocycles substituted at the C-2 position by a carbonyl group functionality. A study of the factors that control this process reveals that the reactivity depends on the presence of electron-donor groups in the aryl ring of the aryloxycarbonylic and arylthiocarbonylic moieties.
- Labarrios, Ehecatl,Jerezano, Alberto,Jimenez, Fabiola,Del Carmen Cruz, Maria,Delgado, Francisco,Zepeda, L. Gerardo,Tamariz, Joaquin
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p. 954 - 971
(2014/08/05)
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- DEVELOPING POTENT URATE TRANSPORTER INHIBITORS: COMPOUNDS DESIGNED FOR THEIR URICOSURIC ACTION
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A compound represented by the general Formula (I): a pharmaceutically acceptable salt or ester thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a pro-drug thereof, a deuterated radio-labeled analog thereof, and mixtures of any of the foregoing, wherein: A - K are individually selected from carbon or nitrogen; X = -O, -NR1,or -S; R1-11 are individually selected from the group consisting of-H, C1-C6 alkyl, C6-C aryl, substituted C6-C14 aryl, C1-C14-alkoxy, halogen, hydroxyl, carboxy, cyano, C1-C6-alkanoyloxy, C1-C6-alkylthio, C1-C6-alkylsulfonyl, trifluoromethyl, hydroxy, C2-C6-alkoxycarbonyl, C2-C6-alkanoylamino, -O-R12, S-R12,-SO2-Ri2, -NHSO2R12 and -NHCO2R12, wherein R12 is phenyl, naphthyl, or phenyl or naphthly substituted with one to three groups selected from C1-C6-alkyl, C6-C10 aryl,C1-C6-alkoxy and halogen, and C4-C20 hydroxyheteroaryl wherein the heteroatoms are selected from the group consisting of sulfur, nitrogen, and oxygen.
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Page/Page column 13
(2012/04/23)
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- Developing potent human uric acid transporter 1 (hURAT1) inhibitors
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The kidneys are a vital organ in the human body. They serve several purposes including homeostatic functions such as regulating extracellular fluid volume and maintaining acid-base and electrolyte balance and are essential regarding the excretion of metabolic waste. Furthermore, the kidneys play an important role in uric acid secretion/reabsorption. Abnormalities associated with kidney transporters have been associated with various diseases, such as gout. The current study utilized Xenopus oocytes expressing human uric acid transporter 1 (hURAT1; SLC22A12) as an in vitro method to investigate novel compounds and their ability to inhibit 14C-uric acid uptake via hURAT1. We have prepared and tested a series of 2-ethyl-benzofuran compounds and probed the hURAT1 in vitro inhibitor structure-activity relationship. As compared to dimethoxy analogues, monophenols formed on the C ring showed the best in vitro inhibitory potential. Compounds with submicromolar (i.e., IC 50 1000 nM) inhibitors were prepared by brominating the corresponding phenols to produce compounds with potent uricosuric activity.
- Wempe, Michael F.,Jutabha, Promsuk,Quade, Bettina,Iwen, Timothy J.,Frick, Morin M.,Ross, Ian R.,Rice, Peter J.,Anzai, Naohiko,Endou, Hitoshi
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experimental part
p. 2701 - 2713
(2011/06/25)
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- An efficient synthesis of benzofuran derivatives under conventional/non-conventional method
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1-Methyl-3-ethyl imidazolium bromide [meim]Br/basic alumina (Al2O3) has been found to promote the cyclocondensation of chloroacetone/chloroethyl acetate with salicylaldehydes under conventional as well as microwave irradiation to yield benzofuran derivatives.
- Sapkal, Suryakant B.,Shelke, Kiran F.,Shingate, Bapurao B.,Shingare, Murlidhar S.
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experimental part
p. 1439 - 1442
(2011/10/09)
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- Preparation of leukotriene B4 inhibitory active 2- and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives and their growth inhibitory activity on human pancreatic cancer cells
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A series of 2-(2-aminothiazol-4-yl)benzo[b]furan and 3-(2-aminothiazol-4- yl)benzo[b]furan derivatives were prepared, and their leukotriene B4 inhibitory activity and growth inhibitory activity in cancer cell lines were evaluated. Several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT1 and BLT2 receptors and growth inhibition to human pancreatic cancer cells MIA PaCa-2. 3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl] -5-methoxybenzo[b]furan 8b showed the most potent and selective inhibition for the human BLT2 receptor, and its IC50 value was smaller than that of the selected positive control compound, ZK-158252. 3-(4-Chlorophenyl)-2-[2-[(dimethylamino)methyleneamino]-5-(2- hydroxyethyliminomethyl)thiazol-4-yl]-5-methoxybenzo[b]furan 9a displayed growth inhibitory activity towards MIA PaCa-2. The Royal Society of Chemistry.
- Kuramoto, Mari,Sakata, Yoko,Terai, Kumi,Kawasaki, Ikuo,Kunitomo, Jun-Ichi,Ohishi, Takahiro,Yokomizo, Takehiko,Takeda, Seiichi,Tanaka, Shuichi,Ohishi, Yoshitaka
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experimental part
p. 2772 - 2781
(2009/02/02)
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- An efficient synthesis of benzofurans and their application in the preparation of natural products of the genus Calea
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The intramolecular cyclization of the β-substituted olefins methyl 2-aryloxy-3-dimethylaminopropenoates 3a-3f catalyzed by Lewis acids leads to a short and novel synthesis of benzofurans 2a-2f. When the olefins 4-dimethylamino-3-aryloxy-3-buten-2-ones 4a-4f were used, the cyclization process was faster and provided the corresponding substituted 2-acetylbenzofurans 1a-1f. Among the latter, naturally occurring compounds calebertin (1a), caleprunin A (1b), and caleprunin B (1c) were prepared in good overall yields. These benzofurans were also obtained by direct treatment under MW irradiation of the precursors 1-aryloxypropan-2-ones 7a-7c with DMFDMA, followed by addition of the catalyst, resulting in a route that was one step shorter.
- Del Carmen Cruz, María,Tamariz, Joaquín
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p. 10061 - 10072
(2007/10/03)
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- Studies in Potential Antifertility Agents : Part XXXI- Synthesis of Substituted 3-(2'-Benzofuranyl)-2,2-dimethylalkanoic Acids
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Some substituted 3-(2'-benzofuranyl)-2,2-dimethylalkanoic acids (29-34) have been synthesized as the heterocyclic analogs of 2,2-dimethyl-3-alkanoic acids (3 and 4) which have been reported earlier to possess significant anti-implantation activity in rats.All the saturated acids and one of the unsaturated acids synthesized show total prevention of implantation in rats when administered on days 1-7 post-coitum.Compounds 24, 29, 30, 31, 33 and 34 have been found to be active at a dose of 5, 5, 5, 10, 2.5, 20 and 0.5 mg/kg, respectively. 34 is also active at a single dose of 5 mg/kg when administered on day 1 of pregnancy.The estrogenic activity of 34 has been observed at 50 μg/kg and 100 μg/kg in uterotrophic and vaginal cornification assays respectively.
- Rao, K. V. B.,Iyer, R. N.
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p. 992 - 995
(2007/10/02)
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