939-90-2Relevant academic research and scientific papers
Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1
Zhou, Chao,Wu, Fangrui,Lu, Lianghao,Wei, Liping,Pai, Eric,Yao, Yuan,Song, Yongcheng
, (2017/02/15)
Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B. Several cyclopropylamine containing compounds were found to be highly potent and selective inhibitors of LSD1. A novel series cyclopropylimine compounds also exhibited strong inhibitory activity against LSD1.Structure activity relationships (SAR) of these compounds are discussed. Docking studies were performed to provide possible binding models of a representative compound in LSD1 and MAO-A. Moreover, these modeling studies can rationalize the observed SARs and selectivity.
Synthesis and in vitro evaluation of novel N-cycloalkylcarbamates as potential cholinesterase inhibitors
Horáková, Eva,Drabina, Pavel,Br??ková, Lenka,?těpánková, ?árka,Vor?áková, Katarína,Sedlák, Milo?
, p. 2143 - 2153 (2017/09/25)
Abstract: This present paper describes the preparation and characterization of a series of O-substituted N-cycloalkylcarbamate derivatives. These compounds were tested as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). All studied carbamates exhibited moderate inhibitory activity of both cholinesterases with values of IC50 in the range of 36.1–78.6?μM for AChE and 9.8–215.4?μM for BChE, respectively. These values are comparable with those values of inhibition obtained with the established drug rivastigmine. The cytotoxicity of all carbamates was evaluated using standard in vitro test with Jurkat cells. Many of the studied carbamates can be considered as promising compounds for potential medicinal applications with regard to their inhibitory activity as well as negligible cytotoxicity.
The synergistic effect of copper chromite spinel nanoparticles (CuCr2O4) and basic ionic liquid on the synthesis of cyclopropanecarboxylic acids
Ghasemi, Mohammad Hadi,Kowsari, Elaheh
, p. 7963 - 7975 (2016/11/25)
Abstract: An efficient synthesis of cyclopropanecarboxylic acids using copper chromite spinel nanoparticles and basic ionic liquid is described. In this study, a relatively simple method starting with trans-cinnamic acid for the synthesis of (±)-trans-2-phenylcyclopropanecarboxylic acid, a key intermediate in the synthesis of tranylcypromine sulfate as an active pharmaceutical ingredient, was employed. Using a combination of basic ionic liquid [Bmim]OH and copper chromite spinel nanoparticles as a catalytic system, the best results were obtained in THF as a polar solvent. This method is a useful alternative to other approaches described in the literature. The use of commercially available chemicals, decreased environmental hazards, with no need for the separation of stereoisomers, and consequently a reduced number of overall steps, are the advantages of this approach that make it an appropriate choice at an increased scale. Graphical Abstract: [Figure not available: see fulltext.]
Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent
Vianello, Paola,Botrugno, Oronza A.,Cappa, Anna,Dal Zuffo, Roberto,Dessanti, Paola,Mai, Antonello,Marrocco, Biagina,Mattevi, Andrea,Meroni, Giuseppe,Minucci, Saverio,Stazi, Giulia,Thaler, Florian,Trifiró, Paolo,Valente, Sergio,Villa, Manuela,Varasi, Mario,Mercurio, Ciro
, p. 1501 - 1517 (2016/03/08)
We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic.
Synthesis, characterization and in vitro evaluation of substituted N-(2-phenylcyclopropyl)carbamates as acetyl- and butyrylcholinesterase inhibitors
Horáková, Eva,Drabina, Pavel,Bro?, B?etislav,?těpánková, ?árka,Vor?áková, Katarína,Královec, Karel,Havelek, Radim,Sedlák, Milo?
, p. 173 - 179 (2016/12/16)
A serie of O-substituted N-2-phenylcyclopropylcarbamates was prepared and characterized. These carbamates were tested as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). It was found, that these compounds exhibit moderate inhibition activity with values of IC50 in the range of 54.8–94.4 μM (for AChE) and up to 5.8 μM (for BChE). The AChE/BChE selectivity for each carbamate was calculated. These values varied from 0.50 to 9.46, two carbamate derivatives inhibited only AChE selectively. The most promising derivative was prepared in all optically pure forms (four isomers). It was found that individual stereoisomers differed only slightly in the inhibition ability. The cytotoxicity of all carbamates was evaluated using the standard in vitro test with Jurkat cells. With regard to their inhibition activity and cytotoxicity as well as easy preparation, O-substituted N-2-phenylcyclopropylcarbamates can be considered as promising compounds for potential medicinal applications.
Nickel-Catalyzed Reductive Carboxylation of Cyclopropyl Motifs with Carbon Dioxide
Moragas, Toni,Martin, Ruben
, p. 2816 - 2822 (2016/08/26)
A nickel-catalyzed reductive carboxylation technique for the synthesis of cyclopropanecarboxylic acids has been developed. This user-friendly and mild transformation operates at atmospheric pressure of carbon dioxide and utilizes either organic halides or alkene precursors, thus representing the first example of catalytic reductive carboxylation of secondary counterparts lacking adjacent π-components.
The influence of cosolvent concentration on enzymatic kinetic resolution of trans-2-phenyl-cyclopropane-1-carboxylic acid derivatives
Wi?niewska, Catalina,Koszelewski, Dominik,Zysk, Ma?gorzata,Ostaszewski, Ryszard
, p. 98 - 104 (2015/08/11)
A method to improve the enantioselectivity of lipase-catalyzed kinetic resolution (KR) of trans-2-phenyl-cyclopropane-1-carboxylic acid derivatives in water-acetone solution is presented. Two different approaches were compared: enzyme-catalyzed esterification and enzymatic hydrolysis of the target ester. A substantial influence of enzyme type, ethoxy group donor, and solvent on conversion and enantioselectivity of the enzymatic esterification was noted. While enzymatic esterification proceeds with poor enantioselectivity, the hydrolysis of target ester proceeds efficiently. Studies on the influence of cosolvent used for the enzymatic hydrolysis reaction showed that kinetic resolution can be performed in acetone and water buffer mixture predominantly containing organic solvent. Any change in organic solvent content resulted in a substantial decrease in enantioselectivity from almost E = 150 to less than 5.
SERINE/THREONINE PAK1 INHIBITORS
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Page/Page column 90, (2013/03/26)
Compounds having the formula I wherein A, Z, R1a, R1b, R2, R3, R4, R5, R6, R7, R9, R10, Ra, Rb and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
(HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS
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Page/Page column 140; 152; 153, (2013/05/09)
The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection.
Silver-promoted, palladium-catalyzed direct arylation of cyclopropanes: Facile access to spiro 3,3′-cyclopropyl oxindoles
Ladd, Carolyn L.,Sustac Roman, Daniela,Charette, André B.
, p. 1350 - 1353 (2013/05/09)
The Pd-catalyzed, Ag(I)-mediated intramolecular direct arylation of cyclopropane C-H bonds is described. Various spiro 3,3′-cyclopropyl oxindoles can be obtained in good to excellent yields from easily accessible 2-bromoanilides. The kinetic isotope effect was determined and epimerization studies were conducted, suggesting that the formation of a putative Pd-enolate is not operative and that the reaction proceeds via a C-H arylation pathway.
