- Novel sulfonamide-containing 2-indolinones that selectively inhibit tumor-associated alpha carbonic anhydrases
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Human carbonic anhydrases IX and XII are upregulated in many tumors and form a novel target for new generation anticancer drugs. Here we report the synthesis of novel 2-indolinone derivatives with the sulfonamide group as a zinc binding moiety. Enzyme inh
- Karal?, Nilgün,Akdemir, Atilla,G?kta?, Füsun,Eraslan Elma, P?nar,Angeli, Andrea,K?z?l?rmak, Merih,Supuran, Claudiu T.
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Read Online
- Novel benzenesulfonamide-bearing pyrazoles and 1,2,4-thiadiazoles as selective carbonic anhydrase inhibitors
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Two series comprising 20 novel benzenesulfonamides bearing thioureido-linked pyrazole 8 and amino-1,2,4-thiadiazole 10 were synthesized and assayed as human carbonic anhydrase (hCA) inhibitors against isoforms I and II as well as the tumor-associated isof
- Kumar, Rajiv,Kumar, Amit,Ram, Sita,Angeli, Andrea,Bonardi, Alessandro,Nocentini, Alessio,Gratteri, Paola,Supuran, Claudiu T.,Sharma, Pawan K.
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- Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors
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Multi-target, especially dual-target, drug design has become a popular research field for cancer treatment. Development of small molecule dual-target inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. In this study, three series of quinazoline derivatives bearing a benzene-sulfonamide moiety were designed and synthesized as dual EGFR/CAIX inhibitors. All the synthesized compounds were evaluated against epidermoid carcinoma (A431) and non-small cell lung cancer (A549 and H1975) cell lines, which displayed weak to potent anticancer activity. In particular, compound 8v emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib. Importantly, 8v exhibited stronger anti-proliferative activity than osimertinib against H1975 cells under hypoxic condition. Kinase inhibition studies indicated that 8v showed excellent inhibitory effect on EGFRT790M enzyme, which was 41 times more effective than gefitinib and almost equal to osimertinib. Mechanism studies revealed that 8v exhibited remarkable CAIX inhibitory effect comparable to acetazolamide and significantly inhibited the expression of p-EGFR as well as its downstream p-AKT and p-ERK in H1975 cells. Notably, 8v was found to inhibit the expression of CAIX and its upstream HIF-1α in H1975 cells under hypoxic condition. Molecular docking was also performed to gain insights into the ligand-binding interactions of 8v inside EGFRWT, EGFRT790M and CAIX binding sites.
- Zhang, Bin,Liu, Zhikun,Xia, Shengjin,Liu, Qingqing,Gou, Shaohua
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- Phospholipid hydroperoxide glutathione peroxidase activating agents and application
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The invention discloses a type of phospholipid hydroperoxide glutathione peroxidase (GPX4) activating agents and application. A structural formula I of the activating agents is as shown in the specification, wherein X refers to a straight chain or branche
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Paragraph 0069; 0070; 0072
(2018/02/04)
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- Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII
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Three series of novel heterocyclic compounds (3a-3g, 4a-4g and 5a-5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozymes hCA I and II, compounds of two series (3a-3g and 4a-4g) showed Ki values in the range of 84-868 nM and 5.6-390 nM, respectively whereas compounds of series 5a-5g were found to be poor inhibitors (Ki values exceeding 10,000 nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with Ki values in the range of 2.8-431 nM and 1.3-63 nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a-5g were comparatively less potent but more selective towards hCA IX and XII.
- Sitaram,Celik, Gulsah,Khloya, Poonam,Vullo, Daniela,Supuran, Claudiu T.,Sharma, Pawan K.
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p. 1873 - 1882
(2014/03/21)
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- TRIAZOLE COMPOUNDS AS ANTIVIRALS
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The present invention discloses compounds of Formula I: wherein the variables in Formula I are defined as described herein. Also disclosed are pharmaceutical compositions containing such compounds and methods for using the compounds of Formula I in the prevention or treatment of HCV infection.
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Paragraph 0211
(2014/01/18)
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- 8 - SUBSTITUTED 2 -AMINO - [1,2,4] TRIAZOLO [1, 5 -A] PYRAZINES AS SYK TRYROSINE KINASE INHIBITORS AND GCN2 SERIN KINASE INHIBITORS
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Compounds of the formula I in which R1, R2 and R4 have the meanings indicated in Claim 1, are inhibitors of Syk, and can be employed, inter alia, for the treatment of cancer, rheumatoid arthritis and / or systemic lupus
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Page/Page column 96
(2013/09/12)
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- Diversity-orientated synthesis of 3,5-bis(arylamino)pyrazoles
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The synthesis of differentially-substituted 3,5-bis(arylamino)pyrazoles has not yet been documented. During our investigation, we managed to develop a novel, entirely combinatorial synthesis of 3,5-bis(arylamino)pyrazoles relying on a simple one-pot two-step operation.
- Degorce, Sébastien,Jung, Frédéric H.,Harris, Craig S.,Koza, Patrice,Lecoq, Jonathan,Stevenin, Arnaud
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supporting information; experimental part
p. 6719 - 6722
(2012/01/05)
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- Synthesis, characterization and in vitro antimicrobial activity of novel 2-thioxo-4-thiazolidinones and 4,4′-bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfones
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2-Thioxo-4-thiazolidinones (3a,b) were achieved by cyclocondensation of isothiocyanatosulfonamides (1a,b) with sulfanylacetic acid at reflux temperature in dioxane in the presence of triethylamine. Compound (3a) was exploited to synthesize the versatile hitherto unknown 2-thioxo-4-thiazolidinones (5-10) via its reaction with some electrophiles. Cyclization of 4,4′-diisothiocyanate diphenylsulfone (11) with sulfanylacetic acid furnished 4,4′-bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfone (12) which on treatment with excess 4-methoxybenzaldehyde in refluxing dioxane in the presence of piperidine yielded the bisbenzylidene derivative (13). The novel synthesized compounds were characterized by IR, 1H NMR and mass spectral studies. All the synthesized compounds were screened in vitro for their antibacterial and antifungal activities.
- El-Gaby, Mohamed S.A.,El-Hag Ali, Gameel A.M.,El-Maghraby, Ahmed A.,Abd El-Rahman, Mohamed T.,Helal, Mohamed H.M.
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scheme or table
p. 4148 - 4152
(2009/12/06)
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- Carbonic anhydrase inhibitors: Design of spin-labeled sulfonamides incorporating TEMPO moieties as probes for cytosolic or transmembrane isozymes
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A series of spin-labeled sulfonamides incorporating TEMPO moieties were synthesized by a procedure involving the formation of a thiourea functionality between the benzenesulfonamide and free radical fragment of the molecules. The new compounds were tested as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and showed efficient inhibition of the physiologically relevant isozymes hCA II and hCA IX (hCA IX being predominantly found in tumors) and moderate to weak inhibitory activity against hCA I. Some derivatives were also selective for inhibiting the tumor-associated isoform over the cytosolic one CA II, and presented significant changes in their ESR signals when complexed to the enzyme active site, being interesting candidates for the investigation of hypoxic tumors overexpressing CA IX by ESR techniques, as well as for imaging/treatment purposes.
- Cecchi, Alessandro,Ciani, Laura,Winum, Jean-Yves,Montero, Jean-Louis,Scozzafava, Andrea,Ristori, Sandra,Supuran, Claudiu T.
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scheme or table
p. 3475 - 3480
(2009/04/04)
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- THIAZOLOPYRIMIDINE KINASE INHIBITORS
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The present invention is directed to novel thiazolopyrimidine compounds of Formula (I) or a form or composition thereof, and the use thereof as inhibitors of ATP-protein kinase interactions.
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Page/Page column 70
(2008/06/13)
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- Synthesis, molecular modelling and enzymatic evaluation of (±)3,5-diphenyl-2-thioxoimidazolidin-4-ones as new potential cyclooxygenase inhibitors
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A series of substituted (±)3,5-diphenyl-2-thioxoimidazolin-4-ones was synthesized in order to design new type-2 cyclooxygenase (COX-2) inhibitors. This study has led to molecules which completely inhibit human recombinant COX-2 at 50 μM. Molecular modelli
- Gauthier, Marie P.,Michaux, Catherine,Rolin, Stephanie,Vastersaegher, Caroline,De Leval, Xavier,Julemont, Fabien,Pochet, Lionel,Masereel, Bernard
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p. 918 - 927
(2007/10/03)
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