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New amphiphilic dextran esters were obtained by polysaccharide functionalization with different substituted 1,2,3-triazoles-4-carboxylic acid via in situ activation with N, N′-carbonyldiimidazole. Nitrogen-containing heterocyclic derivatives were achieved by copper(I)-catalyzed cycloaddition reaction between organic azides and ethyl propiolate. Structural characteristics of the compounds were studied by elemental analysis, Fourier transform infrared and nuclear magnetic resonance spectroscopy (1H and 13C‐NMR). Thermogravimetric analysis, differential scanning calorimetry and wide-angle X-ray diffraction were used for esters characterization. Properties of polymeric self-associates, formed in aqueous solution, were studied by dynamic light scattering and transmission electron microscopy. The critical aggregation concentration values for dextran esters, determined by fluorescence spectroscopy, were in the range of 4.1-9.5 mg/dL. Antimicrobial activity, investigated for some of the polymers by disc-diffusion method, pointed out that polysaccharide esters were active. • Dextrans with 1,4-disubstituted 1,2,3-triazoles as side-chains were obtained. • 13C-NMR, FTIR, thermal studies and WAXD were used for esters characterization. • Polymeric self-associates, formed in aqueous media, were studied by DLS and TEM. • CAC for the dextran esters demonstrated lower values (4.1–9.5 mg/dL) • Some of the polymers showed a moderate to good antimicrobial activity. [ABSTRACT FROM AUTHOR]

Triazoles are a class of chemical compounds known for their diversity and usefulness in chemistry and medicine [1,2]. Their structure allows obtaining of a wide range of derivatives [3]. The most widely used method of synthesis of 1,2,3-triazole derivatives is the "Click Chemistry" reaction between azides and marginal alkynes in Cu (I) catalysis [4]. Using a series of four marginal alkynes and 2-azido-1-(4-methoxyphenyl)ethanone (1), the 1,2,3-triazolic derivative (2a) known in the literature and three new derivatives (2b-d) were obtained by the click method. In order to increase the azide transformation yield, changes were made in the synthesis mode, thus establishing the optimal path to obtain the desired triazole derivatives. All synthesized compounds were purified and characterized physically and spectrally (IR, ¹H-NMR, 13C-NMR). [ABSTRACT FROM AUTHOR]

Coumarin (2H-1-benzopyran-2-one) (1) contains an α-pyronic oxygen heterocycle fused with a benzene nucleus and is the basic skeleton of a large class of phenolic derivatives. Due to its pleasant smell, similar to vanilla, coumarin is used in perfumery and cosmetics [1]. Coumarin frame organic compounds are found in plants, with over 1300 coumarin derivatives identified from natural sources [2]. Small molar mass, simple structure, high solubility in organic solvents and high bioavailability make coumarin derivatives usable in research and development of pharmaceutical compounds [3]. Heart diseases, central nervous system disorders, the aging process, and the development of cancer can be caused by excess free radicals. 4-arylcoumarins (2) are reported to have significantly stronger free radical trapping properties than traditional antioxidants, namely vitamin C or vitamin E [4]. Knowing the biomedical potential of 4-arylcoumarins, the most efficient route was pursued to convert 3,4,5-trimethoxyacetophenone into coumarin derivative (3), by converting it to b-ketone ester and then condensation with resorcine in the presence of sulfuric acid. The structure of the obtained compounds was spectrally confirmed (IR, ¹H-NMR, 13C-NMR). [ABSTRACT FROM AUTHOR]

Due to its presence in numerous molecules with pronounced biological activity, the 1,2,3-triazole fragment is an important candidate in medicinal chemistry [1]. The solubility of this azaheterocycle in a polar biological medium, its high chemical stability, and its ability to mimic other groups, make the presence of the 1,2,3-triazole moiety in different molecular architectures of wide interest [2]. To identify new biologically active compounds, the reactions of C-alkylation were performed for 1,2,3-triazoles (3a-c), in the presence of sodium hydride or potassium carbonate as the base and ethyl bromoacetate as the alkylating agent. The 1,2,3-triazoles used in this study were synthesized in two steps from ω-bromoacetophenone in 85-90% yields. (Scheme1) Research has led to the conclusion that the methylene bridge of 3(a-b) triazoles can be alkylated and a suitable reaction mechanism has been proposed. In the case of triazoles 3c, elimination products have been identified. All synthesized compounds were purified and characterized physically and spectrally (IR, ¹H-NMR, 13C-NMR, MS). The structure of derivative 4b was also confirmed by singlecrystal XRD. [ABSTRACT FROM AUTHOR]

1,3-dipolar cycloadditions are commonly used in organic synthesis to obtain heterocyclic skeletons with various medical and technical applications [1]. The study aimed to investigate the chemical behavior of dimethyl fumarate in the presence of 1,3-dipoles generated in situ from 4-substituted pyridinium salts. By alkylation of 4-methylpyridine and N,N-dimethylaminopyridine with ω-bromoacetophenone, the pyridinium salts (1) and (2) were obtained as substrates generating N-ylides in a basic medium. Dimethyl fumarate acts as a good dipolarophile in these reactions and also serves as a reactant in Michael-type additions [2]. After separating the products resulting from the cycloaddition reactions, the lactonization capacity of certain intermediate products was observed, and derivates of octahydro- and decahydropyrrolo[ 2,1,5-cd]indolizine-6-one type obtained through a double 1,3-dipolar cycloaddition were identified [3,4]. [ABSTRACT FROM AUTHOR]

Widespread in nature, cinnamic acid (2E-3-phenylpropenoic acid, Fig. 1) is an α,β-unsaturated carboxylic acid, containing a double bond in the trans configuration and is found mainly in cinnamon oil and shea butter [1]. Our researches were aimed at synthesizing ester derivatives of cinnamic acid, with a propargylic residue, in two stages, using benzoic aldehyde as starting material. Stage I: Attainment of the cinnamic acid by the Perkin condensation between benzoic aldehyde and acetic anhydride in the presence of anhydrous K2CO3 at a temperature of 170˚C (Fig. 1). Stage II: Esterification of cinnamic acid with propargyl alcohol in the presence of the condensing agents CDI and EDC·HCl: The compound of interest (propargyl cinnamate, Fig. 2) obtained was by working method 3, then purified and physically and spectrally characterized. Esterification by working method 3, of ferulic acid (2E-3-(4-hydroxy-3-methoxyphenyl)propenoic acid, Fig. 3), did not lead to the desired propargylic ester [ABSTRACT FROM AUTHOR]

1,2,3-triazole based ligands are widely exploited in therapeutic chemistry, with numerous biological activities, the most important are the anticancer ones [1]. Likewise, metal complexes [2] show interest in this field, therefor the use of coordination compounds with 1,2,3-triazole based ligand could give expected results. The 1,2,3-triazole 1,4-disubstituted derivative, ethyl 1-(2-phenyl-2-oxoethyl)-1H-1,2,3- triazole-4-carboxylate (L), was synthesized by click chemistry. Subsequently, 2 complexes based on Cu(II) were synthesized starting from its salt (CuCl2 ·2H2O) in the presence of MeOH or EtOH by stirring at 40 °C, in the reaction with L in ratio Cu(II):L = 1:2. All the compounds were characterized by IR, UV-VIS spectrometry, conductometric, thermogravimetric and magnetic methods. The ligand was supplementary analyzed by NMR spectrometry. The kinetics of the substitution reaction of coordinated ligand with cysteine was also studied. The cytotoxicity of L, and CuL2 complexes was tested by the MTT method and the cell morphology by evaluating the impact of the complexes and L at 6.25, 12.5, 25 and 50 μM after 24 and 48 h on the normal cell line V79-4 (pulmonary fibroblasts, derived from the Chinese hamster Cricetulus griseus) and the tumor cell line MCF-7 (human mammary adenocarcinoma). DMSO 0.1% was used to solubilize the compounds. The results regarding IC50 after 48 h for MCF-7 were 55.13 for L, 21.73 for CuL2 in MeOH and 54.43 for CuL2 in EtOH. [ABSTRACT FROM AUTHOR]

A mild and efficient α-aza-amidoalkylation for the synthesis of 5-arylaminopyrrolidinones is presented. The key step of this reaction is the intermolecular interception of an N-acyliminium species, generated under the acidic conditions, with nitrogen nucleophiles such as N-silylamines. [ABSTRACT FROM AUTHOR]

The rational structural modification of new substituted indolizin-3-yl(phenyl)methanones 1a – i , 2a – i and 3a – i has greatly improved human farnesyltransferase inhibition. The para -bromophenyl analog 2f bearing an ester unit on the indolizine ring demonstrates the highest inhibition potential, with IC 50 value of 1.3 ± 0.2 μM. The amidic series 1a – i proves to be the most promising for future modulations, particularly at the triple bond level. [ABSTRACT FROM AUTHOR]

A facile synthesis of Pechmann dyes has been accomplished by the reaction of substituted N-phenacyl-4-dimethylaminopyridinium halides with dimethyl maleate in the presence of DBU. Based on a related 4-DMAP elimination product and an isolated monolactone intermediate a reaction mechanism has been proposed. The scope of this synthetic method is determined by the availability of α-haloaroyl or heteroaroyl derivatives. DBU=1,8-diazabicycloundec-7-ene, DMAP=4-dimethylaminopyridine. [ABSTRACT FROM AUTHOR]

The synthesis of dimethoxytriazine-containing V-aryl substituted pyrrolidinones is realized for the first time. Three new modes of reactivity for these substrates possessing a 4,6-dimethoxy-1,3,5-triazine unit are discussed. Their treatment with acid leads to complete O-demethylation of the methoxy groups, while similar re-action in a basic medium leads to partial O-demethylation. In con-trast, heating in the presence of dimethyl sulfate as the catalyst induces migration of the methyl groups from the oxygen atoms to the triazine nitrogens (Hilbert-Johnson transposition). These new scaffolds may demonstrate biological potential. [ABSTRACT FROM AUTHOR]

Abstract: The biological screening of the chemical library of our Organic Chemistry Department, carried out on an automated fluorescence-based FTase assay, allowed us to discover that a phenothiazine derivative (1d) was an inhibitor of farnesyltransferase. Three new series of human farnesyltransferase inhibitors, based on a phenothiazine scaffold, were synthesized with protein farnesyltransferase inhibition potencies in the low micromolar range. Ester derivative 9d was the most active compound in these series. Four synthesized compounds were evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. The modest results obtained in this preliminary investigation showed that mixing the phenothiazine and the 1,2,3-triazole motif in the structure of a single compound can lead to new scaffolds in the field of farnesyltransferase inhibitors. [Copyright &y& Elsevier]

A direct and highly selective synthesis of octahydropyrrolo[ 2,1,5-cd]indolizin-6-one derivatives has been accomplished by a double dipolar cycloaddition of olefinic dipolarophiles to p-(dimethylamino) pyridinium ylides. [ABSTRACT FROM AUTHOR]

The reaction of 10-azidoacetyl-10 H-phenothiazine with olefinic dipolarophiles depends on the reaction temperature. In refluxing toluene, a mixture of enamine and aziridine is formed in 3:1 ratio. The reaction mechanism appears to involve a Michael-type addition of the nucleophilic N azide atom to the olefinic double bond. In chloroform, a cycloaddition reaction takes place with the formation of a 4,5-dihydro-1,2,3-triazole. The heating of dihydrotriazoles in toluene is accompanied by nitrogen elimination leading to a mixture of enamine and aziridine in 1:3 ratio. J. Heterocyclic Chem., 2011. [ABSTRACT FROM AUTHOR]

Phenothiazine derivatives of type (III) and (IV) are prepared using click chemistry approach. [ABSTRACT FROM AUTHOR]

The primary products of the double 1,3-dipolar cycloaddition of pyridinium ylides to olefins (II) are the tricyclic enamines (IV). [ABSTRACT FROM AUTHOR]

A new family of indolizine–chalcones was designed, synthesized and screened for the inhibitory potential on human farnesyltransferase in vitro to identify potent antitumor agents. The most active compound was phenothiazine 2a , exhibiting an IC 50 value in the low nanomolar range, similar to that of known FTI-276, highly potent farnesyltransferase inhibitor. The newly synthesized indolizine–chalcones 2a – d constitute the most efficient inhibitors of farnesyltransferase bearing a phenothiazine unit known to date. [ABSTRACT FROM AUTHOR]

A new family of CaaX competitive inhibitors of human farnesyltransferase based on phenothiazine and carbazole skeleton bearing a l -cysteine, l -methionine, l -serine or l -valine moiety was designed, synthesized and biologically evaluated. Phenothiazine derivatives proved to be more active than carbazole-based compounds. Phenothiazine 1b with cysteine residue was the most promising inhibitor of human farnesyltransferase in the current study. [ABSTRACT FROM AUTHOR]

A new family of 3-aroylindolizines bearing a dimethoxytriazine unit in their position 1 was designed, synthesized and evaluated for their ability to inhibit tubulin polymerization and cellular growth in vitro. Compound 39 was the best candidate in the current study with a GI 50 value of 870 nM on SNB-75 CNS cancer cells and of 920 nM on MDA-MB-231/ATCC breast cancer cells. The standard NCI Compare results indicated that indolizine 39 may target PLK1 (polo-like kinase 1). [ABSTRACT FROM AUTHOR]

Abstract: A simple one-pot approach for the synthesis of new pyrazolones containing a phenothiazine unit is reported. Compound 4b was evaluated for its antiproliferative activity on a NCI-60 cancer cell line panel and exhibited selective cytostatic activity toward CCRF–CEM, HL-60(TB), K-562, MOLT-4, and RPMI-8226 leukemia cell lines. [Copyright &y& Elsevier]

Abstract: Novel phenothiazine derivatives bearing an amino acid residue were synthesized via peptide chemistry, and evaluated for their inhibitory potential on human farnesyltransferase. The phenothiazine unit proved to be an important bulky unit in the structure of the synthesized inhibitors. Propargyl ester 20 bearing a tyrosine residue exhibited the best biological potential in vitro in the present study. Further syntheses and biological evaluation of phenothiazine derivatives are necessary in order to gain a full view of SAR in this family of farnesyltransferase inhibitors. [Copyright &y& Elsevier]

Abstract: A new family of microtubule-targeting agents with a phenothiazine A-ring was synthesized and evaluated for anti-proliferative activity and interaction with tubulin. These new derivatives showed significant activities against cellular proliferation and tubulin polymerization, rather similar to those of phenstatin. Phenothiazine derivative 21 proved to be the most potent compound synthesized with GI50 values ranging from 29 to 93nM on different cell lines. The same compound showed a better inhibition of COLO 205, A498, and MCF7 cell lines than the parent phenstatin. [Copyright &y& Elsevier]

Abstract: A new family of protein farnesyltransferase inhibitors, based on a phenothiazine scaffold, was designed and synthesized. The biological evaluation of these products showed that compounds 28 and 30 were the most active, with protein farnesyltransferase inhibition potencies in the low micromolar range. Compounds were also evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. Indenopyrazole 30 exhibited the most potent in vitro cytostatic activity inhibiting the growth of HCT-116, LOX IMVI and SK-MEL-5 cell lines. [Copyright &y& Elsevier]