- Cathepsin B inhibitors: Further exploration of the nitroxoline core
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Human cathepsin B is a cysteine protease with many house-keeping functions, such as intracellular proteolysis within lysosomes. Its increased activity and expression have been strongly associated with many pathological processes, including cancers. We present here the design and synthesis of novel derivatives of nitroxoline as inhibitors of cathepsin B. These were prepared either by omitting the pyridine part, or by modifying positions 2, 7, and 8 of nitroxoline. All compounds were evaluated for their ability to inhibit endopeptidase and exopeptidase activities of cathepsin B. For the most promising inhibitors, the ability to reduce extracellular and intracellular collagen IV degradation was determined, followed by their evaluation in cell-based in vitro models of tumor invasion. The presented data show that we have further defined the structural requirements for cathepsin B inhibition by nitroxoline derivatives and provided additional knowledge that could lead to non-peptidic compounds with usefulness against tumor progression.
- Sosi?, Izidor,Mitrovi?, Ana,?uri?, Hrvoje,Knez, Damijan,Brodnik ?ugelj, Helena,?tefane, Bogdan,Kos, Janko,Gobec, Stanislav
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supporting information
p. 1239 - 1247
(2018/03/05)
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- Investigation of the antimycobacterial activity of 8-hydroxyquinolines
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A series of styrylquinolines and quinolineamides based on the 8-hydroxyquinoline moiety were investigated as potential antimycobacterial agents. The lipophilicity of the compounds was measured using RP-HPLC and the tests of their activity against Mycobacterium kansasii, the M. avium complex, M. smegmatis, M. abscessus, M. tuberculosis and M. avium paratuberculosis was performed. Several of the compounds that were obtained appeared to be more effective than isoniazid and ciprofloxacin. The 5,7-dinitro-8-hydroxyquinoline derivative possessed the highest potency against M. abscessus and M. Smegmatis, which was about twice as effective as ciprofloxacin, while 2-(2-hydroxystyryl)-8-hydroxyquinoline-7-carboxylic acid appeared to be comparable with the standard drugs that are against the M. avium complex. The structure activity relationships are discussed.
- Cieslik, Wioleta,Spaczynska, Ewelina,Malarz, Katarzyna,Tabak, Dominik,Nevin, Eoghan,O'Mahony, Jim,Coffey, Aidan,Mrozek-Wilczkiewicz, Anna,Jampilek, Josef,Musiol, Robert
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p. 771 - 779
(2015/12/01)
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- Substituted oxines inhibit endothelial cell proliferation and angiogenesis
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Two substituted oxines, nitroxoline (5) and 5-chloroquinolin-8-yl phenylcarbamate (22), were identified as hits in a high-throughput screen aimed at finding new anti-angiogenic agents. In a previous study, we have elucidated the molecular mechanism of antiproliferative activity of nitroxoline in endothelial cells, which comprises of a dual inhibition of type 2 human methionine aminopeptidase (MetAP2) and sirtuin 1 (SIRT1). Structure-activity relationship study (SAR) of nitroxoline offered many surprises where minor modifications yielded oxine derivatives with increased potency against human umbilical vein endothelial cells (HUVEC), but with entirely different as yet unknown mechanisms. For example, 5-nitrosoquinolin-8-ol (33) inhibited HUVEC growth with sub-micromolar IC50, but did not affect MetAP2 or MetAP1, and it only showed weak inhibition against SIRT1. Other sub-micromolar inhibitors were derivatives of 5-aminoquinolin-8-ol (34) and 8-sulfonamidoquinoline (32). A sulfamate derivative of nitroxoline (48) was found to be more potent than nitroxoline with the retention of activities against MetAP2 and SIRT1. The bioactivity of the second hit, micromolar HUVEC and MetAP2 inhibitor carbamate 22 was improved further with an SAR study culminating in carbamate 24 which is a nanomolar inhibitor of HUVEC and MetAP2. The Royal Society of Chemistry 2012.
- Bhat, Shridhar,Shim, Joong Sup,Zhang, Feiran,Chong, Curtis Robert,Liu, Jun O.
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supporting information; experimental part
p. 2979 - 2992
(2012/05/07)
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- X-ray and molecular modelling in fragment-based design of three small quinoline scaffolds for HIV integrase inhibitors
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Crystal structures of three small molecular scaffolds based on quinoline, 2-methylquinoline-5,8-dione, 5-hydroxy-quinaldine-6-carboxylic acid and 8-hydroxy-quinaldine-7-carboxylic acid, were characterised. 5-Hydroxy- quinaldine-6-carboxylic acid was co-crystallized with cobalt(II) chloride to form a model of divalent metal cation-ligand interactions for potential HIV integrase inhibitors. Molecular docking into active site of HIV IN was also performed on 1WKN PDB file. Selected ligand-protein interactions have been found specific for active compounds. Studied structures can be used as scaffolds in fragment-based design of new potent drugs.
- Majerz-Maniecka, Katarzyna,Musiol, Robert,Skorska-Stania, Agnieszka,Tabak, Dominik,Mazur, Pawel,Oleksyn, Barbara J.,Polanski, Jaroslaw
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scheme or table
p. 1606 - 1612
(2011/04/16)
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- QUINOLINE COMPOUNDS AS INHIBITORS OF ANGIOGENESIS, HUMAN METHIONINE AMINOPEPTIDASE, AND SIRT1, AND METHODS OF TREATING DISORDERS
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Described herein are methods of inhibiting methionine aminopeptidase or SirT1, inhibiting angiogenesis, and treating disorders (or symptoms thereof) associated with methionine aminopeptidase, SirT1 and/or angiogenesis, wherein a compound of the invention
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Page/Page column 69
(2010/04/28)
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- Investigating biological activity spectrum for novel quinoline analogues
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The lack of the wide spectrum of biological data is an important obstacle preventing the efficient molecular design. Quinoline derivatives are known to exhibit a variety of biological effects. In the current publication, we tested a series of novel quinol
- Musiol, Robert,Jampilek, Josef,Kralova, Katarina,Richardson, Des R.,Kalinowski, Danuta,Podeszwa, Barbara,Finster, Jacek,Niedbala, Halina,Palka, Anna,Polanski, Jaroslaw
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p. 1280 - 1288
(2008/03/12)
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- Lavendamycin analogues and methods of synthesizing and using lavendamycin analogues
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Lavendamycin analogues, methods for their synthesis, and methods for their use in the treatment of diseases such as cancer and HIV infection are described.
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Page/Page column 17
(2010/10/20)
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- Antifungal properties of new series of quinoline derivatives
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The series of quinoline derivatives were prepared. The synthetic approach, analytical, and spectroscopic data of all synthesized compounds are presented. All the prepared derivatives were analyzed using the reversed-phase high performance liquid chromatog
- Musiol, Robert,Jampilek, Josef,Buchta, Vladimir,Silva, Luis,Niedbala, Halina,Podeszwa, Barbara,Palka, Anna,Majerz-Maniecka, Katarzyna,Oleksyn, Barbara,Polanski, Jaroslaw
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p. 3592 - 3598
(2007/10/03)
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- Highly efficient and practical syntheses of lavendamycin methyl ester and related novel quinolindiones
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The novel 7-(N-formyl-, 7-(N-acetyl-, and 7-(N-isobutyrylamino)-2-methylquinoline-5,8-diones were synthesized in excellent overall yields in three steps via the nitration of the commercially available 8-hydroxy-2-methylquinoline followed by a reduction-acylation step and then oxidation. Acid hydrolysis of 7-(N-acetylamino)-2-methylquinoline-5,8-dione (14a) afforded the novel 7-aminoquinoline-5,8-dione 7 in excellent yields. Due to our efficient preparation of dione 14a, we now report a short and practical method for the total synthesis of the potent antitumor agent lavendamycin methyl ester (1b) with an excellent overall yield.
- Behforouz, Mohammad,Haddad, Jalal,Cai, Wen,Arnold, Macklin B.,Mohammadi, Farahnaz,Sousa, Aron C.,Horn, Mark A.
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p. 6552 - 6555
(2007/10/03)
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