Chemical Synthesis

Delafossite CuAlO 2 p-type nanostructured semiconductor was synthesized using boehmite (-AlOOH) nanorods loaded with copper(I) acetate [Cu(OAc)] as a precursor (nanoprecursor). Because Cu(OAc)-loaded -AlOOH nanorods are highly anisotropic, they tend to form inherent bunches consisting of several nanorods during the course of drying the nanoprecursor dispersion droplet on a solid substrate. By annealing the nanoprecursor at 1150 ºC in air, a delafossite CuAlO 2 polycrystal was successfully obtained as the dominant phase. The CuAlO 2 polycrystal is found to exhibit the (110) crystal orientation. The crystalline anisotropy of CuAlO 2 , which is not usually attainable using conventional molecular precursors, is presumably originated in the anisotropic morphology of the nanoprecursor. The Seebeck coefficient, resistivity and thermal conductivity of the CuAlO 2 polycrystal at 300 K were found to be +560 μV•K 1 , 1.3 Ω•m and 19.4 W•K 1 •m 1 , respectively, confirming the p-type nature of the CuAlO 2 polycrystal.

Al-doped ZnO (AZO) nanoparticles (NPs) have been synthesized via the thermal decomposition of metal acetylacetonate precursors in a nonoxygen and nonpolar solvent. Long-chain alkyl amines have been utilized to terminate the growth of AZO NPs and to stabilize them. The NPs have been characterized by a number of techniques as monocrystalline, exhibiting a hexagonal (wurtzite) structure with sizes from 8 to 13 nm. The composition of Al in the resulting NP is related solely to the composition of the reaction mixture and the size is controllable with the temperature of the reaction. The AZO NP dispersion has been proven to be stable over a 24 h period by dynamic light scattering measurements. The influence of the synthetic conditions, such as temperature, reaction time and the Al doping content, on the properties of NPs have also been investigated. An optically transparent AZO thin film was fabricated using the AZO nanoink by spin casting followed by annealing. The resulting film resisti...

General Details: All reactions were performed in oven-dried (120 o C) or flame-dried glass apparatus under dry N 2 or argon atmosphere. The solvents were dried and distilled from the indicated drying agents: CH 2 Cl 2 and CHCl 3 from P 2 O 5 ; THF and Et 2 O from sodium/benzophenone; toluene, benzene and hexanes from sodium; DMSO and DMF from CaH 2 . Sodium hydride (NaH) (55% in oil) and n-butyl lithium (1.6 M in hexanes) were obtained from Aldrich. Vanillin was obtained from Spectrochem (India). Tetrabutylammonium fluoride trihydrate and tetrabutylammonium chloride were obtained from Fluka. Compounds 5a,b, [1] 6a,b, [1] 7a-c, [2] 11, [3] Pd(dba) 2 , [Pd(allyl)Cl] 2 , 4-acetamidoiodobenzene [6] and 1-iodo-2-methoxy-4-methylbenzene [6] were prepared following the literature procedures. Iodobenzene, 4iodoanisole, 1-iodonaphthalene, 4-iodotoluene were obtained from Lancaster. 1 H NMR and 13 C NMR spectra were recorded on a Bruker 200 MHz/500 MHz spectrometers. Spectra were referenced to residual chloroform (δ 7.25 ppm., 1 H; 77.00 ppm, 13 C). Chemical shifts are reported in ppm (δ); multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), quint (pentet), m (multiplet) and br (broad). Coupling constants, J, are reported in Hertz. Mass spectra were recorded on a Fisons VG Quatro II mass spectrometer (EI 70 V; CI 30 V; ESI 3.5 KV). Infrared spectra (IR) were recorded on a Nicolet Impact 410 FT IR spectrophotometer in NaCl cells or in KBr discs. Peaks are reported in cm -1 . Melting points (m.p.) were determined on a Fischer John's melting point apparatus and are uncorrected. Analytical thin-layer chromatography was performed using home made silica gel plates (0.5 mm). A mixture of vanillin (15 g, 98.68 mmol, 1 equiv), benzyl bromide (12.2 mL, 101.97 mmol, 1.03 equiv), tetrabutylammonium iodide (4.9 g, 13.16 mmol, 0.133 equiv) and anhydrous K 2 CO 3 (18.4 g, 131.24 mmol, 1.33 equiv) in DMF (132 mL) was stirred at 47 ºC under argon atmosphere. After 24 h, the reaction mixture was diluted with cold water and extracted with ether. The extract was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography followed by crystallization (hexane-EtOAc) to give product 13 (32 g, 87%). M.p. 72-73 ºC; R f

A novel series of conformationally-restricted oxazolidinones was synthesized which possess a fused pyrazole ring substituted with various alkyl, aryl and heteroaryl substituents. A number of analogs exhibited potent activity against both Gram-positive and fastidious Gram-negative organisms.

In order to reveal the real intermediate in the base-promoted reaction of 1, 3-bromo-4,4-dideuterio-6,7benzobicyclo[3.2.1]octa-2,6-diene 10 was synthesized and its HBr elimination reaction studied. Reaction of 10 with potassium tert-butoxide yielded butoxyl ether 18 in which proton-deuterium exchange has occured.

Bromination of benzonorbornadiene (1) with sodium bromide in the presence of sodium perborate at room temperature gave only one product, the dibromide 2 produced via Wagner-Meerwein rearrangement. However, at high temperatures, bromination resulted predominantly in the formation of rearranged solvolytic products whose formation mechanisms are discussed.

The molybdenum cofactor is composed of a molybdenum coordinated by one or two rather complicated ligands known as either molybdopterin or pyranopterin. Pterin is one of a large family of bicyclic N-heterocycles called pteridines. Such molecules are widely found in Nature, having various forms to perform a variety of biological functions. This article describes the basic nomenclature of pterin, their biological roles, structure, chemical synthesis and redox reactivity. In addition, the biosynthesis of pterins and current models of the molybdenum cofactor are discussed.

Glucosamine sulfate (SGlc) has been known to be effective in controlling osteoarthritis (OA) symptoms in several clinical studies. However, the mechanisms of this positive effect of SGlc in human OA still remain elusive. Therefore, first, the effects of SGlc on the differentiation of osteoblast-like MG-63 cells were investigated. Our results demonstrate that SGlc can increase ALP activity, collagen synthesis, osteocalcin secretion, and mineralization in osteoblastic cells in vitro. Furthermore, it was observed that SGlc exhibited anti-inflammatory effect on production of TNF-a, IL-1b, and PGE 2 in macrophage, RAW264.7 cells. In conclusion, these results suggest that SGlc can promote cell differentiation in cultured MG-63 osteoblast cells via anti-inflammatory effect.

Simple and efficient photoacid generators (PAGs) for carboxylic and sulfonic acids based on N-acyl-N-phenylhydroxylamines have been demonstrated. Irradiation of o-carboxylates and thermally rearranged o-arenesulfonates of N-acyl-N-phenylhydroxylamines using UV light (!254 nm) in aqueous methanolic solution resulted in efficient generation of carboxylic and sulfonic acids, respectively. The carboxylic acid generation ability of N-acyl-N-phenylhydroxylamines was found to be dependent on their N-acyl substituents. Further, polymer bearing o-arenesulfonates of N-acyl-N-phenylhydroxylamine was synthesized and demonstrated as PAG for sulfonic acids.

Phenotypes are established by thigh regulation on protein functions. This regulation can be mediated allosterically, through protein binding, and covalently, through post-translational modification (PTM). The integration of an ever-increasing number of PTMs into regulatory networks enable and define the proteome complexity. Protein PTMs can occur enzymatically and non-enzymatically. Polyphosphorylation, a recently discovered PTM that belongs to the latter category, is the covalent attachment of the linear ortho-phosphate polymer called inorganic polyphosphate (polyP) to lysine residues. PolyP, which is ubiquitously present in nature, is also known to allosterically control protein function. To date, lack of reagents has prevented the systematic analysis of proteins covalently and/or allosterically associated with polyP. Here we report on the chemical synthesis of biotin-modified monodisperse short chain polyP (bio-polyP8-bio) and its subsequent use to screen a human proteome array t...

We previously demonstrated that piperazinyl-linked fluoroquinolone dimers possess potent antibacterial activity against drug-resistant strains of Staphylococcus aureus. In this study, we report the preparation and evaluation of a series of incomplete dimers toward ascertaining structural features of piperazinyl-linked ciprofloxacin dimers that render these agents refractory to fluoroquinolone-resistance mechanisms in Staphylococcus aureus.

The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on their excellent bactericidal properties on aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position of the imidazole ring is required for aerobic activity. Here we show that substitution of this oxygen by either nitrogen or sulfur yielded equipotent analogs. Acylating the amino series, oxidizing the thioether, or replacing the ether oxygen with carbon significantly reduced the potency of the compounds. Replacement of the benzylic oxygen at the 6-position by nitrogen slightly improved potency and facilitated exploration of the SAR in the more soluble 6-amino series. Significant improvements in potency were realized by extending the linker region between the 6-(S) position and the terminal hydrophobic aromatic substituent. A simple 4-feature QSAR model was derived to rationalize MIC results in this series of bicyclic nitroimidazoles.

RESUMEN: En este trabajo se reporta la síntesis del material híbrido polimetilmetacrilato (PMMA)/sílice mesoporosa SBA16. El monómero metacrílico es adsorbido por la sílice y posteriormente polimerizado mediante tratamiento térmico, empleando como iniciador peróxido de benzoilo. El porcentaje en peso adsorbido es determinado empleando espectroscopia ultravioleta y su conversión a PMMA es seguida mediante espectroscopia infrarroja con transformada de Fourier. La disminución en el área superficial y en los diámetros de poro, además de la ausencia de una temperatura de transición vítrea, confirman que las macromoléculas se encuentran ocluidas en los canales del sólido. La inserción del polímero al interior de la estructura mesoporosa, origina una red orgánica inorgánica interpenetrada, convirtiendo a este compuesto molecular en un potencial agente reforzante para matrices poliméricas basadas en metacrilatos.

We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.

Lamellarin α and six different types of lamellarin α 20-sulfate analogues were synthesized and their structure-activity relationships were investigated using a single round HIV-1 vector infection assay. All lamellarin sulfates having pentacyclic lamellarin core exhibited anti-HIV-1 activity at a 10 µM concentration range regardless of the number and position of the sulfate group. On the other hand, non-sulfated lamellarin α and ring-opened lamellarin sulfate analogues did not affect HIV-1 vector infection in similar concentrations. The lamellarin sulfates utilized in this study did not exhibit unfavorable cytotoxic effect under the concentrations tested (IC50 > 100 µM). Confocal laser scanning microscopic analysis indicated that hydrophilic lamellarin sulfates were hardly incorporated in the cell. HIV-1 Env-mediated cell-cell fusion was suppressed by lamellarin sulfates. These results suggested that lamellarin sulfates have a novel anti-HIV-1 activity besides the previously reported integrase activity inhibition, possibly at a viral entry step of HIV-1 replication.

Titration of copper acetate solution with a dilute NaOH solution to pH 6.5 and subsequent aging at 313 K yielded copper hydroxide acetate with an analytical composition of Cu2(OH)3.1(OCOCH3)0.9nH2O (n ∼ 0.7) and layered discoid crystals. The chemical composition, structure, and holistic trend in thermal behavior are similar to those of the previously known Cu2(OH)3(OCOCH3)H2O phase with layered rectangular crystals. The most obvious difference between the two compounds is morphology of the crystals. The other major differences are found in stability of bonding of the interlayer acetate ions to solid phase and behavior in anion-containing solutions. The interlayer acetate ions in the present compound begin to be dissociated from the solid phase at ∼343 K while those in the previous compound are not dissociated below 383 K. The reaction of the present compound is topotactic in Cl− and NO3− aqueous solutions but reconstructive in a SO42− aqueous solution while the reaction of the previ...

Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC 50 values less than 1 mmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fusedring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and

Studies of the structural, magnetic and magnetocaloric properties of polycrystalline Pr 0.6-x Eu x Sr 0.4 MnO 3 (0 ≤ x ≤ 0.15) perovskite manganites were carried out. Substitution for praseodymium with europium, with smaller ionic radius, induces local distortion in the ⟨Mn-O-Mn⟩ bonds and consequently causes a random distribution in the magnetic exchange interactions. The competition between magnetic interactions leads to the appearance of an inhomogeneous magnetic state in our samples. Pr 0.6-x Eu x Sr 0.4 MnO 3 (x = 0, 0.05, 0.1 and 0.15) polycrystalline samples were prepared using the solid-solid reaction method at high temperature. The compounds yielded are single phase and crystallize in the orthorhombic system with the Pnma space group. The substitution of Eu for Pr leads to a decrease of the Curie temperature T C from 303 K for x = 0.00 to 260 K for x = 0.15. All of our compounds exhibit a large magnetic entropy change with a maximum around 2.2 J/kg K under a magnetic applied field change of 2 T for all compounds.

General Comments. All solvents were dried by standard methods and all reactions were carried out under an inert atmosphere. For 1 H and 13 C NMR spectra the deuterated solvents indicated were used. Mass spectrometric data (MS) were obtained by electron ionization (EI, 70 eV), chemical ionization (CI, H 2 O) or electrospray ionization (ESI). For preparative scale chromatography, silica gel (60-200 mesh) was used. Melting points are uncorrected. General procedure for the synthesis of salicylates 3 and 12: To a CH 2 Cl 2 solution of silyl enol ether 2 (1.0 equiv.) and 1,3-bis(silyl enol ether) 1 (1.0 equiv.) was dropwise added TiCl 4 (1.0 equiv.) at -78 o C under argon atmosphere. The solution was stirred at -78 o C for 30 min and then allowed to warm to 20 °C during 18 h. To the solution was added a saturated aqueous solution of NaHCO 3 . The organic layer was separated and the aqueous layer was repeatedly extracted with CH 2 Cl 2 . The combined organic extracts were dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography (silica gel, nhexane/EtOAc) to give salicylates 3. The synthesis of 3a was previously reported. 11a Methyl 4,5,6-trimethyl-2-hydroxybenzoate (3b). Starting with 1-methoxy-1,3-bis-(trimethylsilyloxy)buta-1,3-diene 1a (1.04 g, 4.0 mmol), 2b (0.744 g, 4.0 mmol) and TiCl 4 (0.760 g, 4.0 mmol) in CH 2 Cl 2 (8 mL), 3b was isolated after chromatography (silica gel, n-hexane/EtOAc

The synthesis of novel aza-1,7-annulated indoles was achieved and these were converted to indolocarbazoles that proved to be potent kinase inhibitors. These compounds were also evaluated in a human colon carcinoma cell line and proved to be good antiproliferative agents.

Fourteen N-acetylated and non-acetylated 3,4,5-tri-or 2,5-dimethoxypyrazoline analogs of combretastatin-A4 (1) were synthesized. A non-acetylated derivative (5a) with the same substituents as CA-4 (1) was the most active compound in the series, with IC 50 values of 2.1 and 0.5 lM in B16 and L1210 cell lines, respectively. In contrast, a similar compound with an acetyl group at N1 of the pyrazoline ring (6g) showed poor activity in the cell lines studied. A cell-based assay indicated that compound 5a caused extensive microtubule depolymerization with an EC 50 value of 7.1 lM in A-10 cells while no activity was seen with the acetylated compound. Molecular modeling studies showed that these compounds possess a twisted conformation similar to CA-4 (1).

Seven N-terminus modified derivatives of a previously published minor-groove binding polyamide (f-ImPyIm, 1) were synthesized and the biochemical and biophysical chemistry evaluated. These compounds were synthesized with the aim of attaining a higher level of sequence selectivity over f-ImPyIm (1), a previously published strong minor-groove binder. Two compounds possessing a furan or a benzofuran moiety at the N-terminus showed a footprint of 0.5 lM at the cognate ACGCGT site (determined by DNase I footprinting); however, the specificity of these compounds was not improved. In contrast, PyImPyIm (4) produced a footprint of 0.5 lM but showed a superior specificity using the same technique. When evaluated by thermal melting experiments and circular dichroism using ACGCGT and the non-cognate AAATTT sequence, all compounds were shown to bind in the minorgroove of DNA and stabilize the cognate sequence much better than the non-cognate (except for the non-amido-compound that did not bind either sequence, as expected). PyImPyIm (4) was interesting as the DT m for this compound was only 4 °C but the footprint was very selective. No binding was observed for this compound with a third DNA (non-cognate, ACCGGT). ITC studies on compound 4 showed exothermic binding with ACGCGT and no heat change was observed for titrating the compound to the other two DNA sequences. The heat capacity (DC p ) of the PIPI/ACGCGT complex calculated from the hydrophobic interactions and SASA calculations was comparable to the experimental value obtained from ITC (À146 cal mol À1 K À1 ). SPR results provided confirmation of the sequence specificity of PyImPyIm (4), with a K eq value determined to be 7.1 • 10 6 M À1 for the cognate sequence and no observable binding to AAATTT and ACCGGT. Molecular dynamic simulations affirmed that PyImPyIm (4) binds as a dimer in an overlapped conformation, and it fits snugly in the minor-groove of the ACGCGT oligonucleotide. PyImPyIm (4) is an especially interesting molecule, because although the binding affinity is slightly reduced, the specificity with respect to f-ImPyIm (1) is significantly improved.

Five polyamide derivatives with rationally modified C-terminus moieties were synthesized and their DNA binding specificity and affinity determined. A convergent approach was employed to synthesize polyamides containing an alkylaminopiperazine (4 and 5), a truncated piperazine (6), or an alkyldiamino-C-terminus moiety (7 and 8) with two specific objectives: to investigate the effects of number of potential cationic centers and steric bulk at the C-terminus. CD studies confirmed that compounds 4, 5, 7, and 8 bind in the minor groove of DNA. The alkylpiperazine containing compounds (4 and 5) showed only moderate binding to DNA with DT m values of 2.8 and 8.3 °C with their cognate sequence, respectively. The alkyldiamino compounds (7 and 8) were more impressive producing a DT m of >17 and >22 °C, respectively. Compound 6 (truncated piperazine) did not stabilize its cognate DNA sequence. Footprints were observed for all compounds (except compound 6) with their cognate DNA sequence using DNase I footprinting, with compound 7 producing a footprint of 0.1 lM at the expected 5 0 -ACGCGT-3 0 site. SPR analysis of compound 7 binding to 5 0 -ACGCGT-3 0 , 5 0 -ACCGGT-3 0 , and 5 0 -AAATTT-3 0 produced binding affinities of 2.2 • 10 6 , 3.3 • 10 5 , and 1 • 10 5 M À1 , respectively, indicating a preference for its cognate sequence of 5 0 -ACGCGT-3 0 . These results are in good agreement with the footprinting data. The results indicate that steric crowding at the C-terminus is important with respect to binding. However, the number of cationic centers within the molecule may also play a role. The alkyldiamino-containing compounds (7 and 8) warrant further investigation in the field of polyamide research.

The transition metal complexes [η 6 -(2β-carbomethoxy-3β-phenyltropane)]tricarbonylchromium (3) and [η 6 -(2β-carbomethoxy-3β-phenyltropane)][η 5 -(pentamethylcyclopentadienyl)]ruthenium(II) triflate (4) were synthesized from 2β-carbomethoxy-3β-phenyltropane (2, WIN 35,065) to further elucidate the influence of substituents on the 3β-aryl on the affinity of the ligand for cocainebinding sites at the dopamine transporter. The compounds were tested for their ability to displace bound [ 3 H]WIN 35,428 (5) from rat caudate putamen tissue and for their ability to inhibit [ 3 H]dopamine uptake. The binding affinity for 3 was 2-fold greater than those observed for cocaine (1) and 2, while the binding affinity for 4 was found to be 100-fold less than those of 1 and 2. In addition, 3 was equipotent with 1 and 2 in [ 3 H]dopamine uptake inhibition studies, while 4 was 10-fold less potent. The potencies of the complexes 3 and 4 correlated well with the structure-activity relationships of other 2β-carbomethoxy-3β-aryltropane derivatives. These data further support a pharmacophore model in which the region occupied by the aryl ring is a lipophilic pocket with electropositive character.

Background: Oligosaccharide synthesis is becoming increasingly important to industry as diverse therapeutic roles for these molecules are discovered. The chemical synthesis of oligosaccharides on an industrial scale is often prohibitively complex and costly. An alternative, that of enzymatic synthesis, is limited by the difficulty of obtaining an appropriate enzyme. A general screen for enzymes that catalyze the synthesis of the glycosidic bond would enable the identification and engineering of new or improved enzymes. Results: Glycosynthases are nucleophile mutants of retaining glycosidases that efficiently catalyze the synthesis of the glycosidic linkage by condensing an activated glycosyl fluoride donor with a suitable acceptor sugar. A novel agar plate-based coupled-enzyme screen was developed (using a two-plasmid system) and used to select an improved glycosynthase from a library of mutants. Conclusions: Plate-based coupled-enzyme screens of this type are extremely valuable for identification of functional synthetic enzymes and can be applied to the evolution of a range of glycosyl transferases.

Several new indole derivatives were synthesised from β‐brominated dehydroamino acids and arylboronic acids by using a strategy developed in our research group that involves a sequential Suzuki–Miyaura cross‐coupling reaction and a metal‐assisted C–N intramolecular cyclisation. The cyclised products were obtained either by direct cyclisation or by isomerisation followed by cyclisation. The photophysical properties of these compounds were studied in four solvents of different polarity (cyclohexane, diethyl ether, acetonitrile and ethanol). All these compounds have reasonably high fluorescence quantum yields (between 16 and 85 %) and show different solvent sensitivity in their fluorescence emission. These results indicate that the indole derivatives prepared are good candidates for fluorescent probes. The response of the new synthesised compounds towards fluoride ion (F–) was evaluated. It was found that methyl 3‐methyl‐1H‐dibenzo[e,g]indole‐2‐carboxylate, methyl 3‐(phenanthren‐9‐yl)‐1...

Two pyrenyl‐dehydroamino acid derivatives were cyclized by a metal‐assisted C–N intramolecular cyclization developed in our research group, to give a pyrenylindole and a phenalenoindole. The pyrenylindole was inserted into a peptide by solid‐phase coupling, with use of a 2‐chlorotrityl chloride resin and a Fmoc strategy. The photophysical properties of the pyrenylindole and phenalenoindole in several solvents were studied and showed that these compounds can be used as fluorescence probes. The results obtained with the peptide labelled with the pyrenylindole moiety show potential for use of this compound as a fluorescence label avoiding the aggregation propensity of pyrene compounds. Photophysical studies of the pyrenylindole and of the phenalenoindole in lipid membranes were also carried out. Steady‐state fluorescence anisotropy measurements revealed that both compounds adopt locations inside the lipid bilayers and are able to report the transition between the gel and liquid‐crystal...

There is great interest in the development of antimicrobial peptides as a potentially novel class of antimicrobial agents. Several structural determinants are responsible for the antimicrobial and cytolytic activity of antimicrobial peptides. In our study, a new synthetic peptide analog, AamAP1-Lysine from the naturally occurring scorpion venom antimicrobial peptide AamAP1, was designed by modifying the parent peptide in order to increase the positive charge and optimize other physico-chemical parameters involved in antimicrobial activity. AamAP1-Lysine displayed potent antibacterial activity against Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration was in the range of 5 to 15 µM with a 10 fold increase in potency over the parent peptide. The hemolytic and antiproliferative activity of AamAP1-Lysine against eukaryotic mammalian cells was minimal at the concentration range needed to inhibit bacterial growth.

A New Facile Chemoenzymatic Synthesis of Levamisole. -A new synthesis for levamisole, a broad spectrum anthelmintic, is described. Key step is the lipase-mediated hydrolysis of (I) yielding the key intermediate (II) in high enantioselectivity. -(KAMAL*, A.

75 Inventors: Joseph Peter Joseph, Cliffside Park, N.J.; Seymour Bernstein, New City, N.Y. American Cyanamid Company, Stamford, Conn. (21) Appl. No.: 784,202 22 Filed: Apr. 4, 1977 51) Int. Cl’.............................................. A61K 31/70 52 U.S. C. ........................................ 424/180; 536/4; 536/18; 536/53; 536/54; 536/115; 536/118; 536/55 73) Assignee: 11 4,120,954 45) Oct. 17, 1978

Amidoxime and O-substituted derivatives of the bis-alkylamidine 1,12-bis(N,N 0 -acetamidinyl)dodecane were synthesized and evaluated as in vitro and in vivo antimalarial prodrugs. The bis-O-methylsulfonylamidoxime 8 and the bis-oxadiazolone 9 derivatives show relatively potent antimalarial activity after oral administration.

Amidoxime and O-substituted derivatives of the bis-alkylamidine 1,12-bis(N,N 0 -acetamidinyl)dodecane were synthesized and evaluated as in vitro and in vivo antimalarial prodrugs. The bis-O-methylsulfonylamidoxime 8 and the bis-oxadiazolone 9 derivatives show relatively potent antimalarial activity after oral administration.

We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC 50 lower than 7 nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC 50 = 2.2 and 1.8 nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3 mg/kg.

Within the frame of the design of prodrug candidates to deliver a C-alkylamidine antimalarial agent, we showed that specific O-substitutions were needed on the alkylamidoxime structure. Among the newly synthesized molecules, bis-oxadiazolone and bis-O-methylsulfonylamidoxime derivatives induced a complete clearance of parasitemia in mice after oral administration.

Synthesis of modified EDTA and DTPA ligands and determination of their binding affinities for the uranyl cation are described. Thanks to a screening method, based on a chromophoric complex displacement procedure, chelating properties were studied in aqueous media under various pH conditions for evaluation of their in vivo uranyl-removal efficacy. Each ligand showed a more or less pronounced affinity for uranium. Specific ligands based on EDTA or DTPA analogues containing sulfocatecholamide (CAMS) were found to exhibit a significant affinity towards uranyl ion in acidic, neutral or basic conditions.

The synthesis of phosphonate, sulfocatecholamide (CAMS) and hydroxypyridinone (HOPO) binaphtyl ligands is presented. Their binding abilities for uranyl cation were determined by UV spectrophotometry in aqueous media versus pH. These titrations showed that the efficiency of these chelating agents depends on the nature of the chelating group. Each ligand shows a more or less pronounced affinity towards uranium. While the bisphosphonate compound did not show any affinity towards the uranyl ion, the BINHOPO derivative exhibits significant affinity at acidic and neutral pH while the BINCAMS is more efficient at basic pH.

Amminoacidi carbociclici con funzionalità multiple installate sulle varie posizioni anulari, come le strutture polioliche 1-8 di questo studio, rappresentano un insieme molecolare omogeneo e, allo stesso tempo, variato, in cui ciascuna entità può essere vista sotto diverse angolazioni.

In this work we deposited Cu 2 ZnSnS 4 (CZTS) thin films on soda-lime glass (SLG) substrate using electrostatic field-assisted low-cost spray pyrolysis technique. The precursor solution, consisting of Cu 2 Cl, ZnCl 2 , SnCl 4 and thiourea at optimized concentrations, was sprayed onto a heated SLG substrate at a flow rate of 0.33ml/min. Spray deposition was carried out at substrate temperatures of 300℃ with varying precursor concentrations. After deposition of the CZTS thin films, the films were annealed at a temperature of 350℃ in argon atmosphere for 60minutes. The Structural characterization of the annealed CZTS film was carried out by X-ray diffraction (XRD) while the film thickness, micrograph, optical and electrical properties were measured using Veeco Dektak 150 Stylus profiler, Carl Zeiss Optical interference microscope, UV-Vis-NIR spectroscopy and four point probe techniques respectively. The result obtained from the XRD showed a peak at the 2θ position of 31.7200° with a FWHM of 0.3600° and d-spacing of 2.81863Å. The annealed CZTS films exhibited excellent polycrystalline orthorhombic structure from XRD measurements. The average sheet resistance of the films is in the region of 7.264X10 7 Ωsq from a thickness of 100nm under dark conditions. The film micrograph obtained at 1,000x using the Carl Zeiss optical interference microscope showed light agglomeration of grains and voids of sparcely dispersed films.

The deoxygenation and 2'-labeling of a C-ribonucleoside by reductive elimination with tri-n-butyltin hydride[3H] in a one-pot reaction is described. The approach is a safe, simple, efficient, and general method for 2'-labeling ofnucleosides.

Preliminary results towards the synthesis of a corrole-based vitamin B12 analogue are reported. The synthesis of three simple corroles, 5,10,15-triphenylcorrole (TPCrl), 5,10,15-tri(2-nitrophenyl)corrole and 10-(4-methoxyphenyl)-5,15-diphenylcorrole is described. The synthesis of 10-[2-(benzoylamino)phenyl]-5,15-diphenylcorrole (DPAPCrl) suggests that a large, bulky meso substituent can be incorporated into the corrole with no loss of stability or significant decrease in yield. Both TPCrl and DPAPCrl were crystallized and their crystal structure is reported.

Hexacyclic congeners 2 and 3 of palau'amine, which incorporate both guanidine functional groups and have the cis configuration of the azabicyclo[3.3.0]octane core, are prepared in 14 steps from cycloadduct 6. Synthetic access to these analogs allows the first direct comparison of NMR data for hexacyclic diguanidine structures having the originally proposed cis-azabicyclo[3.3.0]octane fragment with data for natural alkaloids of the palau'amine family. This comparison provides convincing evidence in favor of the recently proposed structural revision of these marine alkaloids, fully supporting the trans configuration of the central azabicyclo[3.3.0]octane ring system of palau'amine and congeners. Recently, the isolation and structural elucidation of additional palau'amine congeners has challenged the initial assignment of the relative configuration of palau'amine, leading to the proposal that stereogenic centers C12 and C17 should be inverted (2, Figure ). 4 Most notably, the revised structure 2 contains a highly strained trans-azabicyclo[3.3.0]octane fragment. Herein, we describe the synthesis of hexacyclic palau'amine derivatives 3 and 4 possessing the originally proposed cis-azabicyclo[ 3.3.0]octane central unit. Comparison of these compounds to palau'amine and tetrabromostyloguanidine (5) 4c,5 using NMR spectroscopic and computational methods provides additional evidence for the revised relative configuration 2 of palau'amine. In our approach toward the putative original structure 1 of palau'amine, an intramolecular azomethine imine 1,3-dipolar cycloaddition forms the cis-azabicyclo [3.3.

Fluorescent derivatives of the bisindolylmaleimide inhibitors of protein kinase C (PKC) were synthesized and tested with respect to their inhibitory potency, specificity, and usefulness as fluorescent cytological stains for PKC. Several of the fluorescent bisindolylmaleimide derivatives (fim-1, fim-2, and rim-1) acted as ATP-competitive catalytic site inhibitors and retained much of the potency and specificity of the parental compound. The R6-C1 and the PKCfl1-overexpressing R6-PKC3 cell lines were used for testing fim-1 and rim-1 as cytological stains for PKC. Comparisons showed that the R6-PKC3 cells stained much more brightly than R6-C1 cells. When R6-PKC3 cells were treated with the phorbol ester phorbol 12-myristate 13-acetate (PMA) for 30 min, staining with fim-1 or anti-PKCB1 revealed a dramatic translocation of PKC to the cell periphery. When R6-PKC3 cells were exposed to PMA for 24 h to down-regulate PKC, cytoplasmic staining was drastically reduced. Staining patterns obtained with an antibody specific for PKCfll and with fim-1 were remarkably similar except for mitochondrial staining, which was only seen with fim-1. A closer examination of the mitochondrial staining showed that mitochondria convert from filamentous to punctate shapes and cluster around the nucleus when cells are treated with PMA. This punctate morphology, perinuclear clustering, and staining with fim-1 persists when PKC is down-regulated. Overall, these results indicate that fim-1 and rim-1 can serve as useful fluorescent probes for PKC. The mitochondrial staining may be due to a PKC isoform resistant to downregulation. Protein kinase C (PKC)' is a family of ubiquitous phospholipid-dependent serine/threonine kinases, which play pivotal roles in cellular signal transduction and growth regulation (1, 2). Protein kinase C is regulated by the lipid agonist, diacyl-