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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]

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]

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]

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]

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 synthesis of ethynyldimethoxytriazine 1, an important platform-compound for developing new chemical entities for anticancer research and for other biological applications, is described. Compound 1 was further reacted with azides 5a- i to provide triazin-triazoles 2a- i, which were tested on human farnesyltransferase and on the NCI-60 human tumor cell lines. Synthesis of other dimethoxytriazine derivatives 15 and 16, linked to a sp or a sp carbon atom were also studied. Graphical Abstract: [Figure not available: see fulltext.] [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: New Schiff base dimers based on phenothiazine heterocycle have been obtained with high yield and purity by condensation of 3-formyl-10-methyl-phenothiazine with various amines. The structural characterization was performed by elemental analysis, FTIR, 1D and 2D NMR spectroscopy and single crystal and powder wide angle X-ray diffraction. The obtained compounds have high thermal stability and some of them self-assemble into cubic mesophase and form stable molecular glass. The thermotropic study performed by polarized optical microscopy and differential scanning calorimetry revealed the possibility to control the compound morphology by thermal annealing and blending miscible components. The photophysical characterization indicates green light emission, with good absolute fluorescence quantum yield, large Stokes shift and high purity and fully saturated color. The special thermal behavior and photophysical properties appear to be significantly dependent on the special supramolecular architecture generated by the hockey-stick shape of the imino-phenothiazine mesogenic core. Collectively, the properties of these azomethines provide a starting point for new compounds with great advantages for optoelectronic applications. [Copyright &y& Elsevier]

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]

The paper reports a series of three new PEGylated phenothiazine derivatives which keep the potential of valuable building blocks for preparing eco-materials addressed to a large realm of fields, from bio-medicine to opto-electronics. They were synthetized by connecting the hydrophilic poly(ethylene glycol) to the hydrophobic phenothiazine via an ether, ester, or amide linking group. The successful synthesis of the targeted polymers and their purity were demonstrated by NMR and FTIR spectroscopy methods. Their capacity to self-assembly in water was studied by DLS and UV–vis techniques and the particularities of the formed aggregates were investigated by fluorescence spectroscopy, SEM, AFM, POM and UV light microscopy. The biocompatibility was assessed on normal human dermal fibroblasts and human cervical cancer cells. The synthetized compounds showed the formation of luminescent aggregates and proved excellent biocompatibility on normal cells. In addition, a concentration dependent cytotoxicity against HeLa cancer cells was noticed for the PEGylated phenothiazine containing an ester unit. Unlabelled Image • PEG was successfully grafted on phenothiazine via ether, ester of amide linking unit. • The PEGylated phenothiazines were water soluble and formed stable luminescent aggregates. • They presented in vitro biocompatibility on normal cells. • The ester containing polymer presented concentration dependent cytotoxicity against HeLa cells. [ABSTRACT FROM AUTHOR]

A series of poly(azomethine-phenothiazine)s was synthesized by using the reaction of 10-methyl-phenothiazine-3,7-dicarbaldehyde with diamines containing fluorene chromophore or polyethylene glycol (PEG) flexible spacer. The polymers were structurally characterized by 1 H NMR and FTIR spectral techniques, elemental analysis and wide angle X-ray diffraction. Their thermal properties were monitored by using variable temperature polarized light microscopy whilst their photophysical behaviour was demonstrated by using UV–vis absorption and photoluminescence spectroscopy. All of these polymers were found to emit green light with high quantum yield, in both solution and solid state. The emission efficiency in solid state was further improved by mixing the fluorene containing polymers with the PEG containing one, when continuous films with quantum efficiency of up to 16% were obtained. [ABSTRACT FROM AUTHOR]

A series of seven low molecular weight compounds containing triazole, pyridine-N-oxide, and one substituted aromatic ring linked together by heteroatoms containing spacers was synthesized by click chemistry reaction. The compounds were structurally characterized by FTIR, NMR, as well as single-crystal X-ray diffraction. Their morphologic, thermotropic, and photophysical properties were determined by dynamic light scattering, scanning electron microscopy, atomic force microscopy, polarized light microscopy, UV-vis, and photoluminescence spectroscopy. The triazole derivatives proved to have porous 3D supramolecular architectures determined by an extensive nonclassical hydrogen bonding network. They spontaneously crystallized into long nanofibers and exhibited typical molecular glass behavior, aggregation induced emission as well as crystallization induced emission enhancement. [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]

With the aim of investigating new analogues of phenstatin with an indolizin-3-yl unit, in particular as the B-ring, three new series of compounds ( 6 – 8 , 9 – 34 and 54 ) were synthesized and tested for interactions with tubulin polymerization and evaluated for cytotoxicity on an NCI-60 human cancer cell lines panel. The replacement of the 3′-hydroxy-4′-methoxyphenyl B-ring of phenstatin with substituted indolizine unit results in the conservation of both antitubulin and cytotoxic effect. Indolizines 9 and 17 were the most effective in the present study and showed the highest antiproliferative effect on melanoma cell lines MDA-MB-435 (GI 50 = 30 nM) and could serve as new lead compounds for the development of anti-cancer therapeutics. [ABSTRACT FROM AUTHOR]

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]

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 convenient procedure involves formation of hydrazines from substrates (I) followed by reaction with esters (II). [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: Two new families of human farnesyltransferase inhibitors 13a–m and 14a–d, based on a phenothiazine scaffold, were synthesized. Compounds 14a and 14b were the most promising inhibitors of human farnesyltransferase with IC50 values of 0.7 and 0.6 μM, respectively. [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]

Compounds (IIId), (IIIe), (IIIf), (VIII), and (XII) show inhibitory activity against human farnesyltransferase. [ABSTRACT FROM AUTHOR]

The synthesis of 3,5-dimethoxy-1,3,5-triazines (III) is developed: demethylation and N-methylation of these products is studied. [ABSTRACT FROM AUTHOR]