Maleimide Derivatives Research Articles

Inhibitory Effects of Maleimide Derivatives from the Mycelia of the Fungus Antrodia cinnamomea BCRC 36799 on Nitric Oxide Production in Lipopolysaccharide (LPS)‐Activated RAW264.7 Macrophages

Four new maleimide derivatives, antrocinnamomins E-H (1-4, resp.), together with (3S,4R)-1-hydroxy-3-(4-hydroxyphenyl)-4-(2-methylpropyl)pyrrolidine-2,5-dione (5) and ergosterol were isolated from the mycelia of Antrodia cinnamomea BCRC 36799. The structures were elucidated by 1D- and 2D-NMR spectroscopy, and mass spectrometry. Compounds 1-5 were evaluated for their inhibitory effects on nitric oxide (NO) production by macrophages. Compounds 2 and 4 showed stronger inhibition of NO production than the positive control quercetin.

Radical Copolymerization of Maleimide Derivatives with n-butyl Acrylate and Characterization of Polymers

The free radical initiated copolymerization of n-butyl acrylate with N-[4-N′-(aniline amino-carbonyl) phenyl] maleimide (APM), N-[4-N′-{(4-chlorophenyl) amino-carbonyl) phenyl] maleimide (CPM), N-[4-N′-{(4-methylphenyl) amino-carbonyl} phenyl] maleimide (MPM), and N-[4-N′-{(4-methoxy phenyl) amino-carbonyl) phenyl] maleimide (MePM) was carried out in THF at 65°C. The polymers were characterized by solubility test and intrinsic viscosity. The structure of copolymers was analyzed by FT-IR and 1H-NMR spectroscopy. The thermal behavior of copolymers was studied by TGA. The initial decomposition temperature of copolymer samples was in the range of 200°C to 275°C.

ChemInform Abstract: Efficient Synthesis of Novel Tetrahydropyrrolo[3′,4′:3,4]pyrrolo[2,1‐a]isoquinoline Derivatives via a Simple and Convenient MCR in Aqueous Micellar System.

AbstractA facile synthesis of the title compounds (16 examples) is completed by 1,3‐dipolar cycloaddition of isoquinolinium ylides to phenyl maleimide derivatives.

1:2‐sequence‐regulated radical copolymerization of naturally occurring terpenes with maleimide derivatives in fluorinated alcohol

AbstractNaturally occurring bulky terpenes, such as (+)‐ and (–)‐limonene and (–)‐β‐pinene, were quantitatively copolymerized with maleimide (MI) derivatives (i.e., phenyl‐, cyclohexyl‐, ethyl‐, and unsubstituted‐MI) in PhC(CF3)2OH solvent via selective 1:2‐alternating propagation governed by the penultimate effect, which resulted in 1:2‐sequence regulated polymers with relatively high glass transition temperatures and optical activities. Similar petroleum‐derived bulky olefins possessing cyclohexenyl, cyclohexyl, or additional α‐methyl substituents were copolymerized with phenylmaleimide via preferential 1:2‐alternating propagation with a slightly lower selectivity. A further decrease in the bulkiness of nonpolar olefins increased the 1:1‐alternating sequence. The copolymerization of limonene and acrylonitrile also proceeded approximately via 1:1‐alternating propagation, in which the penultimate effect was less observable. Furthermore, when methylene chloride was used instead of fluorinated alcohol for the copolymerization of limonene and phenylmaleimide, the length of the sequence of MI units increased. Thus, in addition to the characteristic MI skeleton, the bulky and rather specific structure of either limonene or β‐pinene induces 1:2‐selective propagation via the penultimate effect, whereas the fluoroalcohol diminishes the homopropagation of MI via a hydrogen bonding interaction with the MI unit. RAFT copolymerization of limonene and various MI derivatives in PhC(CF3)2OH successfully proceeded to give the end‐to‐end 1:2‐sequence‐regulated copolymer with a selective initiating sequence and predominant capping sequence using an appropriate RAFT agent. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013

MI1 – derivative of maleimide inhibits cell cycle progression in tumor cells of epithelial origin

MI1 – derivative of maleimide inhibits cell cycle progression in tumor cells of epithelial origin

Морфологічні зміни у печінці щурів під впливом похідного малеіміду на фоні хемо-індукованого раку товстої кишки

The morpho-functional state of rat liver under the influence of the maleimide derivative 1-(4-Cl-benzyl)-3-Cl-4-(CF 3 -fenilamino)-1H-pyrrole-2,5-dione (MI-1), 1,2-dimethylhyd­razine (DMH) and MI-1 on the background of DMH-induction colon carcinogenesis has been investigated. It was found that prolonged (20 and 26 weeks) action of MI-1 at 0.027 and 2.7 mg/kg doses of did not cause changes in size of hepatocytes and their nuclei, but certain structural changes are developing in the cytoplasm of hepatocytes and liver stagnation. Under the influence of DMH morphological changes are significant in the liver: changing the structure of the cytoplasm of hepatocytes and their nuclei, cytoplasm of hepatocytes content is shifted to the cell periphery. Only hepatocytes that are directly adjacent to the central vein, have granular cytoplasm, which is uniformly filling the cell. There is thickening of central venous endothelium and vascular wall of the portal tracts, and also inflammation in portal tracts were observed. Hepatocytes and their nuclei were increased indicating the activation of metabolic processes in the liver that are associa­ted with the transformation of DMH. 6 weeks after discontinuation of the DMH is a partial restoration of the structure of the liver were observed. In a joint action, MI-1 and DMH, maleimide derivative reduces the damaging effects of dimethylhydrazine towards rat liver. Under the action of MI-1 at 0.027 mg/kg dose on the background of DMH hepatocytes effects were different reacted – there was a great variability in cell size and their nucleus. MI-1 action at 2.7 mg/kg dose on the background of DMH, the size of hepatocytes and their nucleus in both zones of hepatic lobules were close to the control values. Keywords: liver, maleimide derivative, 1,2-dimethylhydrazine.

Di-heterometalation of thiol-functionalized peptide nucleic acids.

As a proof-of-principle, two hetero-bimetallic PNA oligomers containing a ruthenium(II) polypyridyl and a cyclopentadienyl manganese tricarbonyl complex have been prepared by serial combination of solid-phase peptide coupling and in-solution thiol chemistry. Solid-phase N-terminus attachment of Ru(II)-polypyridyl carboxylic acid derivative, C1, onto the thiol-functionalized PNA backbone (H-a-a-g-t-c-t-g-c-linker-cys-NH 2) has been performed by standard peptide coupling method. As two parallel approaches, the strong affinity of thiols for maleimide and haloacetyl group has been exploited for subsequent post-SPPS addition of cymantrene-based organometallic cores, C2 and C3. Michael-like addition and thioether ligation of thiol functionalized PNA1 (H-gly-a-a-g-t-c-t-g-c-linker-cys-NH 2) and PNA2 (C1-a-a-g-t-c-t-g-c-linker-cys-NH 2) to cymantrene maleimide and chloroacetyl derivatives, C2 and C3, respectively, has been performed. The synthesized ruthenium(II)-cymantrenyl PNA oligomers have been characterized by mass spectrometry (ESI-MS) and IR spectroscopy. The distinct Mn-CO vibrational IR stretches, between 1,924-2,074 cm (-1) , have been used as markers to confirm the presence of cymantrenyl units in the PNA sequences and the purity of the HPLC-purified PNA thioethers assessed using LC-MS.

Aggregation induced emission characteristics of maleimide derivatives

A simple microwave assisted protocol for the construction of maleimides from various anilines and dialkyl acetylene dicarboxylates has been demonstrated. The AIE property of one of the maleimide derivatives has been studied in detail. The maleimide is AIE-active, and its color, fluorescence efficiency, quantum yield and fluorescence lifetime can be readily tuned by adding water to the THF solution. Compound 3a is found to be weakly luminescent when it is dissolved in THF, but its luminescence intensity increases enormously by the gradual addition of water up to 90% with associated increase in quantum yield and fluorescence lifetime.

Microwave-Assisted Synthesis of Organophosphorus Compounds

Kabachnik-Fields reactions of a variety of amines, phospha-Michael additions to maleimide derivatives and alcoholysis of dialkyl phosphites were studied under microwave conditions.

ChemInform Abstract: A Facile and Economical Procedure for the Synthesis of Maleimide Derivatives Using an Acidic Ionic Liquid as a Catalyst.

AbstractA room temperature ionic liquid is applied as recyclable catalyst for the dehydrative cyclization of maleamic acid amides to N‐substituted maleimides.

Efficient synthesis of novel tetrahydropyrrolo[3′,4′:3,4]pyrrolo[2,1-a] isoquinoline derivatives via a simple and convenient MCR in aqueous micellar system

A simple and efficient one-pot three component synthesis of tetrahydropyrrolo[3′,4′:3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione derivatives has been achieved from variously substituted isoquinolines, 2-bromo acetophenone and N-aryl maleimide derivatives in an aqueous micellar medium. The synthesis represents an environmentally benign alternative to classical methods.

In silico classification and virtual screening of maleimide derivatives using projection to latent structures discriminant analysis (PLS-DA) and hybrid docking

In silico screening algorithms are frequently included in drug discovery programs because a significant number of drug candidates have been detected through structure and ligand-based algorithms. In the current work 337 maleimide derivatives that are inhibitors and non-inhibitors of GSK-3α/β were successfully investigated by means of a projection to latent structures discriminant analysis and hybrid docking. These models developed with Dragon (M1) and OpenEye (M2) descriptors are statistically robust (training set M1: R X 2 = 0.677, R Y 2 = 0.976, Q Y 2 = 0.970; M2: R X 2 = 0.651, R Y 2 = 0.835, Q Y 2 = 0.830) and suitably predictive according to Golbraikh–Tropsha external validation criteria (test set M1: R 2 = 0.949; M2: R 2 = 0.835). The models appropriately explained the structural differences between active and inactive compounds in terms of graph topology, substitutional pattern, and molecular flexibility, and predicted false negatives in PubChem assay 1650. The model M2 showed 73.88 % correct external prediction against 264 active maleimides downloaded from ChEMBL. An evaluation of the key interactions with GSK-3β binding site residues was simulated by hybrid docking. A new virtual screening methodology involving equation M2 and hybrid docking was applied to 9,042 maleimide derivatives extracted from PubChem. The model M2 predicted 1,327 active compounds that were subsequently docked into the GSK-3β ATP binding site. Finally 648 compounds were established as hits after the exclusion of previously detected active maleimides. The structural diversity of the new compounds is high demonstrating that the scaffold hopping ability of the current approach is noticeable.

ChemInform Abstract: Microwave‐Assisted Phospha‐Michael Addition of Dialkyl Phosphites, a Phenyl‐H‐phosphinate, and Diphenylphosphine Oxide to Maleic Derivatives.

AbstractA variety of new P‐substituted succinic acid derivatives is synthesized via microwave‐assisted phospha‐Michael addition of phosphites, phosphinates or phosphine oxides to maleimide or maleic acid derivatives.

ChemInform Abstract: Efficient and General Protocol for Sonogashira Cross‐Coupling Reactions of Maleimides.

Maleimides are involved for the first time in Sonogashira cross-coupling reactions. Sonogashira conditions have been developed to allow subsequent coupling of various terminal alkynes at room temperature in moderate to excellent yields. These results open the way to innovative synthesis strategies for various difunctionalized maleimide derivatives.

Synthesis of Nimesulide Based New Class of Succinimide Analogues: Their Evaluation as Potential Cytotoxic Agents

Novel succinimide derivatives based on nimesulide were designed as potential anticancer agents and their synthesis was carried out using a straightforward and atom economic method. The key step of this methodology involved an Aza-Michael addition of several nitrogen nucleophiles to the corresponding N-aryl maleimide derivatives prepared efficiently from nimesulide via a two-step process. A number of compounds containing –NHX (X = Ar, NHCOR, NHAr etc) at the C-3 of the succinimide were prepared in good yields. A number of compounds synthesized were tested for their cytotoxicity in vitro against human colon cancer cell lines and some of them showed promising activities. Keywords: Nimesulide, Succinimide, Aza-Michael addition, Cancer, cytotoxic activities, N-arylsuccinamic acids, cytotoxic succinimide derivatives, N-aryl maleimide, Doxorubicin, acylhydrazides

N-(1-Pyrenyl) maleimide inhibits telomerase activity in a cell free system and induces apoptosis in Jurkat cells

Telomerase activity is repressed in normal human somatic cells, but is activated in most cancers, suggesting that telomerase may be an important target for cancer therapy. Agents that interact selectively with telomerase are anticipated to exert specific action on cancer cells. In this study, we evaluated maleimide derivatives for their potency and selectivity of telomerase inhibition. Among the several N-substituted derivatives of maleimide tested, N-(1-Pyrenyl) maleimide was shown to exert the greatest inhibition of telomerase in a cell free system, with an IC50 value of 0.25 μM. Importantly, we demonstrated that N-(1-pyrenyl) maleimide induces apoptosis in Jurkat T cells and displays the greatest differential cytotoxicity against hematopoietic cancer cells. These results suggest that N-(1-pyrenyl) maleimide is an attractive maleimide to be tested and developed as anti-cancer drug.

ChemInform Abstract: Discovery and Structural Insight of a Highly Selective Protein Kinase Inhibitor Hit Through Click Chemistry.

AbstractNovel bisaryl maleimide derivatives (IV) to mimic natural kinase inhibitors are prepared through click chemistry.

A facile and economical procedure for the synthesis of maleimide derivatives using an acidic ionic liquid as a catalyst

Seven maleimide derivatives were synthesized in good yields and high purity from the corresponding maleamic acids using a Brønsted acidic room temperature ionic liquid (RTIL) as a catalyst. The products were obtained through merely a decanting and removal of the solvent, suggesting that this procedure is superior to the conventional routes, in which the strong organic/inorganic acids were used as the catalysts, as well as a complicated post-processing procedure for the separation and purification of the products was employed.

Identification of specific features of inhibition of PKCβII and its potential lead by shape-based virtual screening and molecular docking studies

Protein kinase C βII (PKCβII) is preferentially expressed during hyperglycemic state resulting in diabetic complications, particularly, diabetic cardiomyopathy. An effective inhibition of PKCβII is a potential option to directly treat the diabetic cardiomyopathy; however, till date no efficient drug targeting PKCβII is available and all the reported PKCβII ligands are maleimide derivatives. The purpose of the present work is to study the importance of the maleimide moiety in PKCβII inhibition and the effects that follow after replacing the maleimide with similar moiety on PKCβII inhibition. For this, an in-house database of maleimide analogues was prepared and shape based screening of commercial databases viz. Specs2009, NCI2003 was performed, followed by filtration using virtual filters. The binding features of reported PKCβII inhibitors, and high scoring hits were analyzed with the help of molecular docking studies. The features identified from the above studies were used for the rational design of new PKCβII inhibitors. The molecular dynamics simulation and ligand–receptor binding affinity studies of the designed molecules has been reported. The toxicity of all the shortlisted and designed molecules was predicted.

Ultrasound assisted copolymerization of acrylonitrile with N-amino phenyl maleimides and N-amino phenyl 2,3 dimethyl maleimides

The N-amino phenyl maleimide (N-APhM) and N-amino phenyl 2,3 dimethyl maleimide (N-APhDiMeM) derivatives were prepared by the condensation of phenyl hydrazine with maleic anhydride and 2,3 dimethyl maleic anhydride respectively. 13C NMR spectroscopy proved the formation of the symmetric amino maleimide structure and not the pyridazinone or aminoisomaleimides.The copolymerization of acrylonitrile with the (N-APhM) and (N-APhDiMeM) were prepared using ultrasound. The thermal behavior of the prepared copolymers, under nitrogen atmosphere, was investigated using thermogravimetry (TG) techniques. The dyeing of the copolymers formed has been studied using both conventional and ultrasonic techniques. The effect of dye bath pH, ultrasonic power, dyeing time and temperature were studied. Color strength values obtained were found to be higher using ultrasound than with conventional heating. The results of fastness properties of the dyed copolymers were also studied.