- 1,5,6,7-Tetrahydro-4H-indazol-4-ones as human neutrophil elastase (HNE) inhibitors
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Human neutrophil elastase (HNE) is a serine protease that is expressed in polymorphonuclear neutrophils. It has been recognized as an important therapeutic target for treating inflammatory diseases, especially related to the respiratory system, but also f
- Bartolucci, Gianluca,Cantini, Niccolo,Crocetti, Letizia,Giovannoni, Maria Paola,Guerrini, Gabriella,Pallecchi, Marco,Quinn, Mark T.,Schepetkin, Igor A.,Teodori, Elisabetta,Vergelli, Claudia
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- Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and in Vitro Metabolic Stability
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Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker γ-H2AX after DHODH inhibition is preventable by cotreatment with the pan-caspase inhibitor Z-VAD-FMK. Additional solubility and in vitro metabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.
- Popova, Gergana,Ladds, Marcus J. G. W.,Johansson, Lars,Saleh, Aljona,Larsson, Johanna,Sandberg, Lars,Sahlberg, Sara H?ggblad,Qian, Weixing,Gullberg, Hjalmar,Garg, Neeraj,Gustavsson, Anna-Lena,Haraldsson, Martin,Lane, David,Yngve, Ulrika,Lain, Sonia
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p. 3915 - 3934
(2020/05/27)
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- Four-Component Domino Synthesis of Pyrazolo[3,4- h]quinoline-3-carbonitriles: "turn-Off" Fluorescent Chemosensor for Fe3+ Ions
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The synthesis of novel pyrazolo[3,4-h]quinoline-3-carbonitriles has been achieved through a one-pot, four-component domino strategy under solvent-free microwave conditions. One of these compounds exhibited fluorescence under UV lamp and was found to be hi
- Shylaja, Adaikalam,Roja, Somi Santharam,Priya, Rakkappan Vishnu,Kumar, Raju Ranjith
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p. 14084 - 14090
(2018/11/30)
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- Pyrazolo[3,4-h]quinolines promising photosensitizing agents in the treatment of cancer
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A new series of pyrazolo[3,4-h]quinolines, heteroanalogues of angelicin was conveniently prepared with a broad substitution pattern. A large number of derivatives was obtained and the cellular photocytotoxicity was evaluated in vitro against 5 different h
- Spanò, Virginia,Parrino, Barbara,Carbone, Anna,Montalbano, Alessandra,Salvador, Alessia,Brun, Paola,Vedaldi, Daniela,Diana, Patrizia,Cirrincione, Girolamo,Barraja, Paola
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p. 334 - 351
(2015/09/01)
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- A novel synthetic approach to 4-acetamido-1-arylindazoles via Semmler-Wolff rearrangement of 1-aryl-6,7-dihydro-5H-indazol-4-one oxime
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A simple and efficient procedure for the syntheses of 4-acetamido-1- arylindazoles from corresponding 1-aryl-6,7-dihydro-5H-indazol-4-one oximes by Semmler-Wolff aromatization using acetic anhydride and sodium iodide is reported.
- Manjunatha, Sulur G.,Bachu, Sreekanth,Kadambar, Vasantha Krishna,Murugan, Andiappan,Ramasubramanian, Sridharan,Ramachandra, Puranik,Nambiar, Sudhir
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p. 3348 - 3350
(2014/06/09)
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- Catalyst-free one-pot synthesis of 1,4,5-trisubstituted pyrazoles in 2,2,2-trifluoroethanol
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A simple, efficient and three component one-pot synthesis of 1,4,5-trisubstituted pyrazoles by condensation of β-dicarbonyls, N,N-dimethylformamide dimethyl acetal (DMFDMA) and hydrazine derivatives in 2,2,2-trifluoroethanol without using any catalyst and activation, is described.
- Alinezhad, Heshmatollah,Tajbakhsh, Mahmood,Zare, Mahboobeh
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experimental part
p. 995 - 1000
(2011/11/06)
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- Sintered silicon carbide: A new ceramic vessel material for microwave chemistry in single-mode reactors
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Silicon carbide (SiC) is a strongly microwave absorbing chemically inert ceramic material that can be utilized at extremely high temperatures due to its high melting point and very low thermal expansion coefficient. Microwave irradiation induces a flow of electrons in the semiconducting ceramic that heats the material very efficiently through resistance heating mechanisms. The use of SiC carbide reaction vessels in combination with a single-mode microwave reactor provides an almost complete shielding of the contents inside from the electromagnetic field. Therefore, such experiments do not involve electromagnetic field effects on the chemistry, since the semiconducting ceramic vial effectively prevents microwave irradiation from penetrating the reaction mixture. The involvement of electromagnetic field effects (specific/nonthermal microwave effects) on 21 selected chemical transformations was evaluated by comparing the results obtained in microwave-transparent Pyrex vials with experiments performed in SiC vials at the same reaction temperature. For most of the 21 reactions, the outcome in terms of conversion/purity/product yields using the two different vial types was virtually identical, indicating that the electromagnetic field had no direct influence on the reaction pathway. Due to the high chemical resistance of SiC, reactions involving corrosive reagents can be performed without degradation of the vessel material. Examples include high-temperature fluorine-chlorine exchange reactions using triethylamine trihydrofluoride, and the hydrolysis of nitriles with aqueous potassium hydroxide. The unique combination of high microwave absorptivity, thermal conductivity, and effusivity on the one hand, and excellent temperature, pressure and corrosion resistance on the other hand, makes this material ideal for the fabrication of reaction vessels for use in microwave reactors. Simulating conductive heat transfer in a microwave: Using reaction vials made out of strongly microwave-absorbing silicon carbide (SiC) in a microwave reactor simulates a conductively heated autoclave experiment due to efficient shielding of the electromagnetic field by the SiC vial. Advantages of SiC vials for microwave processing include their excellent corrosion resistance, thermal stability, and high thermal effusivity and conductivity.
- Gutmann, Bernhard,Obermayer, David,Reichart, Benedikt,Prekodravac, Bojana,Irfan, Muhammad,Kremsner, Jennifer M.,Kappe, C. Oliver
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supporting information; experimental part
p. 12182 - 12194
(2011/02/23)
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- Microwave chemistry in silicon carbide reaction vials: Separating thermal from nonthermal effects
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Running oil-bath chemistry in a microwave! Using reaction vials made out of strongly microwave-absorbing silicon carbide (SiC) in a microwave reactor simulates experiments conducted in an autoclave with conductive heating because of the efficient shielding of the electromagnetic field by the SiC vial. This technology makes it possible to study the significance of microwave effects.
- Obermayer, David,Gutmann, Bernhard,Oliver Kappe
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supporting information; scheme or table
p. 8321 - 8324
(2010/01/06)
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- Aqueous one-pot synthesis of pyrazoles, pyrimidines and isoxazoles promoted by microwave irradiation
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Microwave irradiation promotes the conversion of enaminoketones formed in situ into a variety of heterocycles by reaction with the appropriate bidentate nucleophile. The advantages of the method over previous approaches are short reaction times and facile purification by precipitation of the products in aqueous media. Moreover the convenient one-pot procedure makes these syntheses particularly suitable for library production. Organic reactions in aqueous media have become of great interest as water is not only more environmentally friendly, but also because organic reactions in water often display unique reactivity and selectivity.
- Molteni, Valentina,Hamilton, Matthew M.,Mao, Long,Crane, Christine M.,Termin, Andreas P.,Wilson, Dean M.
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p. 1669 - 1674
(2007/10/03)
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- Reaction of 2-Dimethylaminomethylene-1,3-diones with Dinucleophiles. I. Synthesis of 1,5-Disubstituted 4-Acylpyrazoles
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Reaction of open-chain and cyclic sym-1,3-diones with N,N-dimethylformamide dimethyl acetal gave, generally in high yield, a series of sym-2-dimethylaminomethylene-1,3-diones which reacted with phenylhydrazine and methylhydrazine to afford, generally in satisfactory yield, a number of 1,5-disubstituted 4-acylpyrazoles.The applications and limits of this new pyrazole synthesis are presented and discussed.
- Schenone, Pietro,Mosti, Luisa,Menozzi, Giulia
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p. 1355 - 1361
(2007/10/02)
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