Chemical Synthesis

This study considers the effects of hydrostatic pressure on the line position and fluorescence lifetime for 5 D 0 → 7 F 2 transitions in Ga 3 Ga 5 O 12 doped with Eu 3+ nanoparticles. The results indicate that the pressure induced lines red shift towards longer wavelengths for all considered lines with different rate. The fluorescence lifetime rapidly decreases with pressure from an ambient pressure up to about 20 kbar and after that it is essentially unchanged up to the end of the considered pressure range. High pressure induced red-shift and fluorescence lifetime can be explained by a simple model. A satisfactory agreement between measured and theoretical predicted lines position and was obtained.

Ca 1-x Sr x SnO 3 powders (x = 0, 0.25, 0.50, 0.75 and 1) were synthesized by the polymeric precursor method. This method is derived from the Pechini one, being quite simple, yielding a high chemical homogeneity. This work aims at evaluating the influence of the modifier (Sr 2+ and/or Ca 2+ ) on the properties of stannates with perovskite structure. The powders were characterized by XRD, Raman and FTIR. The increase of the Sr 2+ concentration in the Ca 1-x Sr x SnO 3 system promotes a high short range organization between the polyhedra, diminishing the high degree of distortions of CaSnO 3 orthorhombic perovskite. On the other hand, it was verified that the samples that with a higher concentration of Ca 2+ show a higher short range organization within the polyhedra (SnO 6 ). As a consequence pure SrSnO 3 presents higher long range order, crystallizing at lower temperature.

Vanadia supported on titanium (Ti)-pillared montmorillonite, issued from different Ti-precursors, have been prepared and characterized. The physico-chemical properties of vanadia-doped Ti-pillared clays depend mainly on the nature of Ti-alkoxide precursor. Higher surface areas and the presence of mesoporosity in the Ti-pillared clay samples are due to the organic polyoxycations intercalated between the clay layers. Surface areas diminish with the increase of vanadia content but remain very high in the case of the samples prepared from Ti(OCH 3 ) 4 or Ti(OC 2 H 5 ) 4 precursors. In the selective catalytic reduction (SCR) of NO by NH 3 , the activity necessitates a good balance between acidic and redox properties. Our results show that the nature of Ti-alkoxide precursor and the dispersion of vanadium are the key factors for obtaining this activity.

A suitable dicationic molten salt based on tropine ([(Tropine) 2 C 3 H 5 OH].2Cl) was prepared and characterized by FT-IR, 1 H-NMR, 13 C-NMR, FESEM, CHN, MS and TGA analysis methods. To determine the accurate structure of the catalyst the potential energy surfaces of possible pathways have been explored and the corresponding energy barriers and some of the required NMR chemical shifts have been calculated. On the basis of the Curtin-Hammett principle, Min4bb seems likely to be the main structure and by the comparison of the experimental and calculated NMR chemical shifts, its structure has been elucidated. The calculations have been performed at the DFT (B3LYP) computational levels with a combination of 6-31 + G(d,p) and 6-311G(d,p) basis sets. In continue the application of reagent was investigated in the acceleration of the synthesis of bis-2-amino-4 H-pyrane and spiro-2-amino-4 H-pyran-oxindole derivatives. The considerable features of the introduced procedure are included easy preparation of the catalyst, use of small amounts of the catalyst and simple work-up method. Also, the catalyst can be easily recovered and recycled for at least 5 times.

Efficient methods for the synthesis of aminomethylated azaindole derivatives via domino copper-catalyzed multicomponent coupling and cyclization have been developed. Using various secondary amines and aldehydes, N-substituted 3-ethynyl-4-aminopyridine was converted to substituted azaindoles in moderate to excellent yields. By use of a 3,4diaminopyridine derivative bearing two alkynyl groups, the corresponding pyrrole-fused azaindoles were synthesized by controlled stepwise cyclization.

Bakers' yeast reduction of (2E)-3-(2'-furanyl)-2-methyl-2-propenal yielded the synthetic intermediate, (2S)-3-(2'-furanyl)-2-methylpropanol, of high chiral purity (>97% ee) for the synthesis of the enantiomers of 2,5-dimethylheptadecane and 7-methylheptadecane, two synergistic sex pheromone components of the western hemlock looper (WHL), Lambdina fiscellaria lugubrosa Hulst. In electrophysiological bioassays, (7S)-but not (7R)-7-methylheptadecane elicited strong antennal responses by male WHL antennae. In field trapping experiments, addition of (7S)-but not (7R)-7methylheptadecane to (5R,11S)-5,11-dimethylheptadecane, the major sex pheromone component of WHL, increased attraction. Attraction to (5R, 11S)-5,11-dimethylheptadecane in combination with (7S)-7-methylheptadecane was further enhanced by the addition of (5S)-but not (5R)-2,5-dimethylheptadecane. Similarly, attraction to (5R, 11S)-5,11-dimethylheptadecane combined with (5S)-2,5-dimethylheptadecane increased when (7S)-but not (7R)-7methylheptadecane was added as a third component. We conclude that (7S)-7-methylheptadecane and (5S)-2,5-dimethylheptadecane are the synergistic sex pheromone components of WHL. The synthetic methodology described is applicable to the synthesis of chiral methyl-branched pheromones in other orders of the Insecta, particularly Coleoptera, Diptera and Orthoptera.

We have previously shown that hyperforin, a phloroglucinol derivative found in St. John's wort, behaves as a potent anti-angiogenic compound. To identify the reactive group(s) mainly involved in this anti-angiogenic effect, we have investigated the anti-angiogenic properties of a series of stable derivatives obtained by oxidative modification of the natural product. In addition, in the present work we have studied the role of the four carbonyl groups present in hyperforin by investigating the potential of some other chemically stable derivatives. Methodology/Principal Findings: The experimental procedures included the analysis of the effects of treatment of endothelial cells with these compounds in cell growth, cell viability, cell migration and zymographic assays, as well as the tube formation assay on Matrigel. Our study with hyperforin and eight derivatives shows that the enolized b-dicarbonyl system contained in the structure of hyperforin has a dominant role in its antiangiogenic activity. On the other hand, two of the tested hyperforin derivatives, namely, tetrahydrohyperforin and octahydrohyperforin, behave as potent inhibitors of angiogenesis. Additional characterization of these compounds included a cell specificity study of their effects on cell growth, as well as the in vivo Matrigel plug assay. Conclusions/Significance: These observations could be useful for the rational design and chemical synthesis of more effective hyperforin derivatives as anti-angiogenic drugs. Altogether, the results indicate that octahydrohyperforin is a more specific and slightly more potent antiangiogenic compound than hyperforin.

Modification of the St. John's wort acylphloroglucinol constituent, hyperforin (1), by acylation, alkylation, and oxidation resulted in detrimental effects on the inhibition of the synaptosomal accumulation of serotonin, showing the existence of definite structure-activity relationships in this in vitro test system and highlighting the role of the enolized cyclohexanedione moiety for activity on neurotransmitter reuptake.

Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III β-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All novel C-seco-taxoids exhibited remarkable potency against A2780TC1 and A2780TC3 cell lines, and no cross resistance to cisplatinand topotecan-resistant cell lines, A2780CIS and A2780TOP. Four of those C-seco-taxoids exhibit much higher activities than IDN5390 against paclitaxel-resistant cell lines, A2780ADR, A2780TC1 and A2780TC3. SB-CST-10202 possesses the best all-round high potencies across different drugresistant cell lines. Molecular modeling studies, including molecular dynamics simulations, on the drug-protein complexes of class I and III β-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III β-tubulin. Paclitaxel and docetaxel represent two of the most important chemotherapeutic drugs currently used for the treatment of ovarian cancer, breast cancer, melanoma, non-small cell lung cancer and Kaposi's sarcoma. Upon prolonged exposure to antitumor agents, cancer cells develop mechanisms of drug-resistance, thus becoming progressively less sensitive to the effect of drugs. Higher doses are then required to achieve the same efficacy with consequent increase in systemic toxicity to normal tissues. A great effort has been devoted to overcome these limitations, by studying in detail the mechanisms of drug-resistance and by identifying novel and highly specific anticancer drugs. Nevertheless, an increasingly prominent mechanism of drug resistance, which has not been successfully addressed yet, is related to the overexpression of specific tubulin isotypes. 1-4 Tubulin dimers, derived from different β isotypes have different behaviors in vitro in regard

Synthesis and Biological Evaluation of New Taxoids Derived from 2-Deacetoxytaxinine J. -A small library of DAT-J analogues is prepared and subjected to screening as new potential MDR-reversing agents against multidrug-resistant breast tumor cell lines. Taxoid (I) shows in vitro reversal activity in human mammary carcinoma MDR cell line MCF7-R at very low concentration and reveals a 67% paclitaxel inhibition concentration reduction when tested in combination with paclitaxel. -(BOTTA*, M.;

In vitro Antimalarial Activity of Hyperforin, a Prenylated Acylphloroglucinol. A Structure-Activity Study. -Hyperforin (I), a phenol-like compound which can be easily absorbed orally, is able to inhibit P. falciparum growth at micromolar concentrations. The activity of (I) is not critically dependent on its phenol-like sensitivity to autooxidation. Furthermore, the prenyl double bonds are not necessary for activity. Since related phloroglucinols like the hop β-acids and the enantiomers of usnic acid show only marginal activity, hyperforin is considered as a new antimalarial chemotype. -

The optimisation of molecular properties within a series of 2-amino dihydroquinazoline 5-HT 5A /5-HT 7 receptor ligands resulted in a significantly improved brain-to-plasma ratio, enhancing the pharmacological utility of these compounds. By modulating the lipophilicity and pK a , a 20-fold increase in brain-to-plasma ratio could be achieved, leading to micromolar brain concentrations after oral administration. The enantiomers of one representative of this series of improved compounds were separated, and the configuration of the eutomer was determined by X-ray crystallography.

The synthesis and in vitro structure-activity relationships (SAR) of a series of triazoles as A 2A receptor antagonists is reported. This resulted in the identification of potent, selective and permeable 1,2,4-triazoles such as 42 for further optimization and evaluation in vivo.

A low temperature synthesis method based on the decomposition of urea at 90°C in water has been developed to synthesise fraipontite. This material is characterised by a basal reflection 001 at 7.44 A ˚. The trioctahedral nature of the fraipontite is shown by the presence of a 06l band around 1.54 Å, while a minor band around 1.51 A ˚indicates some cation ordering between Zn and Al resulting in Al-rich areas with a more dioctahedral nature. TEM and IR indicate that no separate kaolinite phase is present. An increase in the Al content however, did result in the formation of some SiO 2 in the form of quartz. Minor impurities of carbonate salts were observed during the synthesis caused by to the formation of CO 3 2-during the decomposition of urea.

A low temperature synthesis method based on the decomposition of urea at 90°C in water has been developed to synthesise fraipontite. This material is characterised by a basal reflection 001 at 7.44 A ˚. The trioctahedral nature of the fraipontite is shown by the presence of a 06l band around 1.54 Å, while a minor band around 1.51 A ˚indicates some cation ordering between Zn and Al resulting in Al-rich areas with a more dioctahedral nature. TEM and IR indicate that no separate kaolinite phase is present. An increase in the Al content however, did result in the formation of some SiO 2 in the form of quartz. Minor impurities of carbonate salts were observed during the synthesis caused by to the formation of CO 3 2-during the decomposition of urea.

A series of trifluoromethyl ketones as SARS-CoV 3CL protease inhibitors was developed. The inhibitors were synthesized in four steps from commercially available compounds. Three different amino acids were explored in the P1-position and in the P2-P4 positions varying amino acids and long alkyl chain were incorporated. All inhibitors were evaluated in an in vitro assay using purified enzyme and fluorogenic substrate peptide. One of the inhibitors showed a time-dependent inhibition, with a K i value of 0.3 lM after 4 h incubation.

Glucose based five arms atom transfer radical polymerization initiator was synthesized. This initiator was used to synthesize 5-arms star polymer of N-vinyl pyrrolidone (NVP) through controlled radical polymerization. The ratio of reactants were kept as 1:1:2: 200 (initiator:Cu(I)Br:bpy:NVP). The rate of reaction with respect to NVP was found to be first order, and number-average molecular weight increases linearly with temperature up to 90 • C. The activation energy (E a = 29.75 kJ mol -1 ) and enthalpy ( H ‡ = 26.73 kJ mol -1 ) were found to be in a good agreement with each other for activated complex, and negative value of entropy of activation ( S ‡ = -219.12 J mol -1 K -1 ) supports the highly ordered transition state.

Abstract: The aim of the present study was to prepare nano-sized ZnS. The ZnS semiconducting nanoparticles were synthesized by simple chemical reaction of Zinc salt like Zinc Acetate [Zn(CH3COO)2], sodium sulfide (Na2S) and DMF [H-CO-N(CH3)2] as a stabilizing agent. The main advantage of this method is to synthesized semiconductor nanomaterials with wide band gap and nanoparticles are chemically stable over a long time. The structural, morphological, chemical composition and optical properties of synthesized nanoparticles have been investigated by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), UV-Vis spectroscopy (UV) and Scanning electron microscopy (SEM). XRD analysis shows that sample prepared were the wrutize structure and the crystallite size estimated using Debey Scherer’s formula was found to be in the range of 35 to 40 nm. The SEM analysis revealed the formation of ZnS nanoparticles with almost spike like shape. In optical characterization the spect...

This Letter describes a new multi-gram synthetic protocol for the preparation of the classic tosylate labeling precursor for the D 2/3 PET agent [ 18 F]fallypride. In the course of our studies, we also discovered two novel labeling precusors, the previously undescribed mesylate and chloro congeners of fallypride.

The kinetics of alkaline hydrolysis of azo reactive dyes: monofunctional with one monohalogeno-s-triazine reactive group and bifunctional with two identical monohalogeno-s-triazine reactive groups was studied in the temperature range from 50 °C to 80 °C by means of high performance liquid chromatography. From the determined pseudo-first order hydrolysis rate coefficients, the chemical reactivity of particular dyes and their sensitivity to temperature changes according to the Arrhenius equation were evaluated. The hydrolysis rate coefficient of monofunctional dyes is more temperature dependent than that of homobifunctional dyes. Reactive dyes with a less reactive monochloro-s-triazine group are more sensitive to temperature variations than reactive dyes with a more reactive monofluoro-s-triazine group. Among the studied dyes, the bis(monofluorotriazine) form of the homobifunctional dye exhibits the lowest sensitivity to temperature variations.

The use of mesoporous gold as electrode material for measurement of electrochemical capacitance is investigated. The electrodes possess a pore size in the range of 10 to 30 nm and are prepared by de-alloying films of AuAl x , where x≥2. Analyses conducted with X-ray photoelectron spectra (XPS) show that their surfaces are essentially pure gold, with only traces of aluminium remaining. The electrodes show near-ideal capacitor behaviour under both cyclic voltammetry and potential-step conditions. The higher capacitance of the mesoporous electrodes leads to a better dynamic range in potential-step experiments, resulting in improved accuracy of measurement. The sensitivity of the new material as a capacitive sensor is demonstrated in a milk fouling experiment, and is improved by up to 30 times compared to the control sample of ordinary planar gold. We propose that the use of mesoporous gold electrodes offer a convenient way to sensitively and accurately amplify the capacitance signal of an electrochemical sensor.

ZnO nanodomains embedded in bimodal mesoporous silica (UVM-7) materials with high Zn content (4 r Si/Zn r 30) have been synthesized by an one-pot surfactant-assisted procedure from a hydro alcoholic medium using a cationic surfactant (CTMABr = cetyltrimethylammonium bromide) as structural directing agent, and starting from molecular atrane complexes of Zn and Si as hydrolytic inorganic precursors. This chemical procedure allows optimizing the dispersion of the ZnO particles in the silica walls. The bimodal mesoporous nature of the final high surface area nano-sized materials is confirmed by XRD, TEM, and N 2 adsorption-desorption isotherms. The small intra-particle mesopore system is due to the supramolecular templating effect of the surfactant, while the large pores have their origin in the packing voids generated by aggregation of the primary nanometric mesoporous particles. A limited pore blocking and a high accessibility to the ZnO active nanoparticles have been achieved. The effects induced by the progressive incorporation of ZnO nanoparticles into the mesostructure have been examined, including a careful optical spectroscopic study (PL and UV-visible).

DHEA analogues with modifications at positions C3 or C17 were synthesized and evaluated for neuroprotective activity against the neural-crest-derived PC12 cell model of serum deprivation-induced apoptosis. The most potent compounds were the spiro-epoxy derivatives 17beta-spiro[5-androstene-17,2'-oxiran]-3beta-ol (20), (20S)-3beta,21-dihydroxy-17beta,20-epoxy-5-pregnene (23), and (20R)-3beta,21-dihydroxy-17alpha,20-epoxy-5-pregnene (27) with IC(50) values of 0.19 +/- 0.01, 99.0 +/- 4.6, and 6.4 +/- 0.3 nM, respectively. Analogues 20, 23, and 27, up to the micromolar range of concentrations, were unable to activate estrogen receptor alpha and beta (ERalpha and ERbeta) or to interfere with ER-dependent gene expression significantly. In addition, they were unable to stimulate the growth of Ishikawa, MCF-7, and LNCaP cells. Our results suggest that the spiro-epoxyneurosteroid derivatives 20, 23, and 27 may prove to be lead molecules for the synthesis of novel neuroprotective agents.

A novel method for the synthesis of N-terminally linked protein multimers is reported. Azide and alkyne thioesters were synthesized for the N-terminal modification of expressed proteins using native chemical ligation (NCL). Proteins modified by these moieties can be joined together to form homodimers and homotrimers via Cu(I)-catalyzed azide-alkyne [3 + 2] cycloaddition (CuAAC) click chemistry. The orthogonal nature of this reaction allows the production of protein heteromultimers, and this is demonstrated by synthesis of a protein heterodimer.

Two hexadeuterated brassinosteroids (BS) ([26,27-2 H 6 ]- 23-dehydroxycastasterone and [26,27-2 H 6 ]-cathasterone) containing a hydroxy group at C 22 instead of the 22R,23R-diol function characteristic for most compounds of this class were prepared for biochemical studies. The corresponding non-deuterated compounds are considered intermediates in brassinolide biosynthesis. The carbon skeleton of the side chain with proper stereochemistry at C 24 was prepared from commercially available (2R)-3-hydroxy-2-methylpropanoate. This low molecular fragment was coupled to the tetracyclic steroidal fragment through the reaction of the appropriate sulfone with C 22 aldehyde. Formation of the necessary configuration of the 22-hydroxy group was achieved by hydride reduction of the corresponding ketone. Deuterium atoms at C 26 and C 27 originated from [ 2 H 3 ]methyl iodide used for alkylation of the intermediate sulfone.

A series of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines were considered as a bioisosteric replacement for the 9-substituted adenine derivatives resulting in the discovery of 8-(2-methoxybenzyl)-4-(N-methylamino)-2-n-propylpyrazolo[1,5-a]-1,3,5-triazine (14d) and 2-trifluoromethyl-8-(2-methoxybenzyl)-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (14e) as a new structural class of potent phosphodiesterase type 4 inhibitors (IC 50 ¼ 13 nM and 11 nM, respectively) with high isoenzyme selectivity. An original tandem of reactions involving a palladium-mediated cross-coupling reaction (PMCCR) of the readily available 8-iodo-2-methyl-4-(N-methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazine (11a) and arylboronic acids or alkynes followed by the displacement of the N-methyl-N-phenylamino group constitute the key steps in a novel synthetic approach developed herein. The treatment of 11aec with n-BuLi and selected aldehydes represents an interesting alternative to the PMCCR for the synthesis of benzylic derivatives 14aei. Preliminary biological testing has shown that compounds 14d and 14e strongly inhibit LPS-induced TNFa release from human mononuclear cells from healthy subjects. These two compounds were selected for further biological evaluation.

A method was found to synthesize 1-( 2,5-dimethoxy-4-(t~uoromethyl)phenyl)-2-a~opropane, 5, and its des-a-methyl congener 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)aminoethane, 6, the trifluoromethyl analogs of substituted hallucinogenic phenethylamine derivatives such as l-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3, DOI) that are potent ~-H T ~A / ~c agonists. In our hands, 5 and 6 have proven to have affinity for [3H]ketanserin or [12511-3-labeled 5-HT,, sites in rat cortex comparable to or higher than the analogous bromo or iodo analogs. Similarly, 5 and 6 had potency comparable to or slightly greater than that of their bromo or iodo congeners in the two-lever drug discrimination assay in rats trained to discriminate saline from LSD tartrate. The agonist properties of 5 and 6 were evaluated by measuring the accumulation of [3H]inositol monophosphate in cultured cells selectively expressing either 5-HTu or 5-HT2c receptors. In comparison to serotonin (5-HT), compounds 3 (DOI), 5, and 6 were equally efficacious and full agonists at the 5-HTzc receptor. Similarly, 3 and 5 produced equivalent responses at the 5-HTu receptor as compared to 5-HT. In contrast, 6, the a-desmethyl analog of 5, was only half as potent at stimulating inositol monophosphate accumulation at the ~-H T ~A receptor. In conclusion, the title compound 5 and its a-desmethyl congener 6 appear to be the most potent of the so-called hallucinogenic amphetamine 5-HT agonists reported to date. Further, the reduced efficacy of 6 at the 5-HTu receptor may offer at least a partial explanation for the observed higher in vivo potencies of a-methyl-substituted compounds in this series.

A morroniside cinnamic acid conjugate was prepared and evaluated on E-selectin mediated cell-cell adhesion as an important role in inflammatory processes. 7-O-Cinnamoylmorroniside exhibited excellent anti-inflammatory activity (IC 50 = 49.3 lM) by inhibiting the expression of E-selectin; further, it was more active than another cinnamic-acid-conjugated iridoid glycoside (harpagoside; IC 50 = 88.2 lM), 7-O-methylmorroniside, and morroniside itself. As a result, 7-O-cinnamoylmorroniside was observed to be a potent inhibitor of TNF-a-induced E-selectin expression.

In this work, we report a rational structure-based approach aimed at the discovery of new 2aminoimidazoles as b-secretase inhibitors. Taking advantage of a microwave-assisted synthetic protocol, a small library of derivatives was obtained and biologically evaluated. Two compounds showed promising activities in both enzymatic and cellular assays. Moreover, one of them exhibited the capability to cross the bloodebrain barrier as assessed by the parallel artificial membrane permeability assay.

A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazolethiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp 3 to sp 2 at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-α-methylcysteine makes the molecule more amenable to chemical synthesis and, coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.

A safe, green and functional-group-tolerant flow version of the direct amide bond formation mediated by Grignard reagents (the Bodroux reaction) is described. The procedure can be applied to a wide variety of primary and secondary amines and anilines, as well as to aromatic and aliphatic esters. The flow approach leads to improved yields and selectivities in the reaction, which has a sustainable purification procedure and a simple scale-up. This reaction represents an efficient and green alternative to the use of alkylaluminium and metal-catalyzed procedures. † Electronic supplementary information (ESI) available: Experimental procedures, GC/MS of representative crude mixtures, GC/MS of the selectivity assays and NMR spectra for all compounds.

A three dimensional quantitative structure activity relationship (3D QSAR) using k nearest neighbor molecular field analysis (kNN MFA) method was performed on a series of arylbenzofuran derivatives as H 3 -receptor antagonists. This study was performed with 29 compounds (data set) using sphere exclusion (SE) algorithm and random selection method for the division of the data set into training and test set. kNN-MFA methodology with stepwise (SW), simulated annealing (SA) and genetic algorithm (GA) was used for building the QSAR models. A predictive model was generated with SW-kNN MFA having internal predictivity 70.55% (q2 = 0.7055) and external predictivity 60.00 % (pred_r2 = 0.60). Model showed that steric (S_579), electrostatic (E_453) and hydrophobic (H_779) interactions play important role in determining H 3 -receptor antagonistic activity. The kNN-MFA contour plots provided further understanding of the relationship between structural features of substituted arylbenzofuran derivatives and their activities which should be applicable to design newer potential H 3 -receptor antagonists.

Imidazolidin-4-ones are commonly employed as skeletal modifications in bioactive oligopeptides, either as proline surrogates or for protection of the N-terminal amino acid against aminopeptidase-and endopeptidase-catalyzed hydrolysis. Imidazolidin-4-one synthesis usually involves the reaction of an R-aminoamide moiety with a ketone or an aldehyde to yield an imine, followed by intramolecular cyclization. We have unexpectedly found that imidazolidin-4-one formation is stereoselective when benzaldehydes containing o-carboxyl or o-methoxycarbonyl substituents are reacted with R-aminoamide derivatives of the antimalarial drug primaquine. A systematic computational and experimental study on the stereoselectivity of imidazolidin-4-one formation from primaquine R-aminoamides and various substituted benzaldehydes has been carried out, and they have allowed us to conclude that intramolecular hydrogen-bonds involving the CdO oxygen of the o-substituent play a crucial role.

The full-length cDNA encoding Perilla frutescens limonene synthase (PFLS) (603 amino acids, GenBank accession no. D49368) was cloned. To elucidate the role of PFLS in gene regulation, we transiently transformed full-length PFLS into tobacco plants. PFLS mRNA was first detected in the intact leaves of the plants at 6 h, and the LS transcript level increased after 12 h in leaves treated with oxidative stress-related chemicals. The transient overexpression of PFLS resulted in increased transcription of NbPR1 and NbSIP in Nicotiana benthamiana leaves. Thus, our result confirmed that the infiltration of PFLS gene act as a transcriptional regulator of NbPR1 or NbSIP genes in the tobacco.

An efficient five-step synthetic method was developed to access a homologous series of spermidineacridine and spermidine-anthracene conjugates. The derivatives were comprised of a spermidine fragment covalently tethered at its N4 position to either an acridine or anthracene nucleus via an aliphatic chain (e.g., spermidine-[aliphatic tether]-acridine). The distance separating the spermidine and aromatic nucleus was altered by using different tethers comprised of four or five methylene units, respectively. These ligands (2-5) were shown to inhibit human DNA topoisomerase-II (TOPO-II) activity at 10 µM. Enzymatic activity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA). Polyamine conjugation did not disrupt the ability of the acridine-spermidine conjugates 2 and 3 to inhibit TOPO-II activity as compared with the 9-aminoacridine and 9-(N-butyl)aminoacridine controls (at 10 µM). In general, the acridine derivatives (2 and 3) showed higher TOPO-II inhibitory activity than their anthracene counterparts (4 and 5). However, this trend was reversed in a whole cell assay with L1210 (murine leukemia) cells, wherein the anthracene analogues were more potent than their acridine counterparts. In this regard the qualitative enzyme-based assay did not predict the trends in the corresponding IC 50 values. Within either series insertion of an additional methylene unit did not significantly alter activity. While the appended spermidine unit did not disrupt TOPO II inhibition by the tethered DNA intercalator, it did provide an alternative mode of entry into the cell as demonstrated by spermidine protection assays. These results were compared with a spermine-intercalator analogue. Of all the conjugates tested the N 4 -(4-(9-aminoacridinyl)butyl)spermine hexahydrochloride (conjugate 16)resulted in the highest degree of L1210 cell rescue upon cotreatment of the cells with exogenous spermidine. It was concluded that the monoalkylated spermine motif present in 16 holds promise as a better vector than its N4 monoalkylated spermidine counterpart.

Over the past 5 years, interest in the miniaturisation of chemical synthesis has grown rapidly, however in order to facilitate transfer of the technology from its current position as a research tool to industrial applications, a core understanding of the challenges associated with transferring reactions from the macro to the micro domain is required. This paper therefore aims to broach this problem by investigating the application of micro reactors to a range of commonly employed synthetic reactions including acylation, aldol, alkylation, 1,4-conjugate addition (Michael addition) and the Knoevenagel condensation. Comparison of the results obtained with traditional batch techniques enable us to highlight some of the advantages associated with micro reaction technology.

We identified and characterized a series of pyrrole amides as potent, selective Cav3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Cav3.1- and Cav3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.

Regarding the pharmacological activities, lignans are mainly known by their cytotoxic activity that is very important in cyclolignans. Nevertheless, these natural products are also inhibitors of AMPc phosphodiesterase, protectors against hepatotoxins and they act on the gastrointestinal tract, cardiovascular system and central nervous system. They have also shown antiinflammatory and antiviral activities, as well as on the platelet activating factor (PAF). Finally, they also have phytoestrogenic properties, that will be described in the third part of these series of papers on lignans.

Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6-12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, β-alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1 RF in CEM-SS cells than they are vs HIV-1 IIIB in MT-4 cells, and they are least potent vs HIV-2 ROD in MT-4 cells.

A series of nitro-substituted N-(benzoylcarbamothioyl)-amino acids (1-4) was synthesized by condensing 3- or 4-nitro-benzoyl isothiocyanate with amino acids (glycine and histidine). These compounds were characterized by HNMR, CNMR, FTIR, and MS. N-(3-nitro- benzoylcarbamothioyl)-glycine was also characterized by single crystal X-ray diffraction study. The compound crystallizes in triclinic space group P-1 with Z=2, a = 3.9354(4) A, b= 12.6015(14) A, c = 16.8149(16) A, α = 71.451(5)°, β = 88.933(3)°, γ = 82.720(3)°. The preliminary antibacterial tests of the compounds gave good activity.

An alternate rapid synthesis of BaFeO 4 is demonstrated. Fe(VI) salts, including BaFeO 4 , are energetic cathode materials in super-iron batteries ranging from primary to secondary, and including aqueous and non-aqueous cells. Of the Fe(VI) salts, BaFeO 4 sustains unusually facile charge transfer, of importance to the high power domain of alkaline batteries. Unlike previous syntheses, BaFeO 4 preparation is demonstrated from all solid state room temperature reactants. This eliminates several synthetic procedural steps and improves stability to approach that of the rigorously stable chemically synthesized K 2 FeO 4 salt.

A very expedient and efficient new route toward taiwaniaquinoids, bearing the 4a-methyltetrahydrofluorene skeleton, is reported. Key steps are the intramolecular Friedel-Crafts alkylation of an aryldiene and the degradative oxidation of a methylenedioxy group; the latter process could also be utilized for building the 2-hydroxy-1,4-benzoquinone unit, which is frequently found in natural products. Utilizing this new methodology, (()-dichroanone (7) (three steps, 77% overall yield) and (()-taiwaniaquinone H (6) (four steps, 70% overall yield) have been synthesized from commercial R-(11a) or β-cyclocitral (11b).

A Short Synthesis of Antimalarial Peroxides. -A short synthesis of two diastereomeric analogues of an natural antimalarial peroxide is reported. The key-step of the synthesis is a Tms-O-Tf catalyzed cyclization of α-silylperoxy ketone (V) to perketals (VI) and (VII). They exhibit moderate antimalarial activity. -(COINTEAUX, L.;

Glucose based five arms atom transfer radical polymerization initiator was synthesized. This initiator was used to synthesize 5-arms star polymer of N-vinyl pyrrolidone (NVP) through controlled radical polymerization. The ratio of reactants were kept as 1:1:2: 200 (initiator:Cu(I)Br:bpy:NVP). The rate of reaction with respect to NVP was found to be first order, and number-average molecular weight increases linearly with temperature up to 90 • C. The activation energy (E a = 29.75 kJ mol -1 ) and enthalpy ( H ‡ = 26.73 kJ mol -1 ) were found to be in a good agreement with each other for activated complex, and negative value of entropy of activation ( S ‡ = -219.12 J mol -1 K -1 ) supports the highly ordered transition state.

Nitrophenyl derivatives were recently discovered as a new class of ALR2 inhibitors by means of docking and database screening of the National Cancer Institute database of organic molecules. The nitro group was predicted to bind to the Tyr48 and His110 active site residues of the enzyme, the site where acidic ALR2 inhibitors such as carboxylic acids bind in their anionic form. Given the novelty of these compounds, we decided to expand their structure-activity relationships by synthesizing and testing a series of derivatives and the corresponding compounds having a carboxylic group instead of the nitro moiety; the results obtained were rationalized by means of docking and molecular dynamics simulations. On the whole there is an agreement between inhibitory data and the results of molecular modeling experiments, supporting the hypothesized binding mode of these compounds.