Preparation of 9-substituted pyridine-stretched adenines and hypoxanthines

9-Methylsulfanyl pyridine-stretched adenine and hypoxanthine derivatives have been prepared via regioselective reaction of a 5-aminoimidazole with 2-(bis-methylsulfanylmethylene)malononitrile [(NC)C=C(SMe) ]. The 9-methylsulfanyl substituent can be replaced by sequential oxidation and substitution by nucleophiles including amines.

Some substituted piperidines of potential biological interest

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Novel anti-bacterials against MRSA:Synthesis of focussed combinatorial libraries of tri-substituted 2(5H)-furanones

Mucobromic and mucochloric acid were used as building blocks for the construction of a chemical combinatorial library of 3,4,5-trisubstituted 2(5H)-furanones. With these 2 butenolide building blocks, and eight alcohols a sublibrary of 16 dihalogenated 5-alkoxy-2(5H)-furanones was prepared. This sublibrary of 5-alkoxylated furanones was reacted with 16 amines generating a full size focussed combinatorial library of 256 individual compounds. This three dimensional combinatorial library of 3-halogen-4-amino-5-alkoxy-2(5H)-furanones was prepared around the benzimidazolyl furanone lead structure by applying a solution phase combinatorial chemistry concept. Typical representatives of the library were purified and fully characterized and one x-ray structures was recorded, additionally. The 3-bromo-4-benzimizazolyl-5-methoxy-2(5H)furanone, Br-A-l, showed an MIC of 8 μg/ml against the multiresistant Staphylococcus aureus ( MRSA). © 2006 Bentham Science Publishers Ltd.

Site-selective direct arylation of unprotected adenine nucleosides mediated by palladium and copper:insights into the reaction mechanism

Reaction conditions facilitating the site-selective direct aryl functionalisation at the C-8 position of adenine nucleosides have been identified. Many different aromatic components may be effectively cross-coupled to provide a diverse array of arylated adenine nucleoside products without the need for ribose or adenine protecting groups. The optimal palladium catalyst loading lies between 0.5 and 5 mol %. Addition of excess mercury to the reaction had a negligible affect on catalysis, suggesting the involvement of a homogeneous catalytic species. A study by transmission electron microscopy (TEM) shows that metal containing nanoparticles, ca. 3 nm with good uniformity, are formed during the latter stages of the reaction. Stabilised PVP palladium colloids (PVP=N-polyvinylpyrrolidone) are catalytically active in the direct arylation process, releasing homogenous palladium into solution. The effect of various substituted 2-pyridine ligand additives has been investigated. A mechanism for the site-selective arylation of adenosine is proposed. © 2008 Elsevier Ltd. All rights reserved.

Antibacterial activity of 3-substituted pyrrole-2,5-diones against Pseudomonas aeruginosa

3-Substituted pyrrole-2,5-diones were synthesised from mucohalogen acids and the antibacterial activity was subsequently determined in biological assays. The minimum inhibitory concentration and the minimum bactericidal concentration of 2a were determined for a wide range of microorganisms in the low micromolar range. Protein identification using SDS-PAGE and LC/MS/MS demonstrated a partly degradation of OprF-related proteins giving an insight into the underlying mechanism of these novel antibacterial agents. © 2007 Bentham Science Publishers Ltd.

Synthesis of substituted 3-anilino-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ones and their evaluation as cholecystokinin-ligands

3-Amino-1,4-benzodiazepines as well as chemically related diverse amines were prepared from oxazepam and subsequently screened on the cholecystokinin receptor in a radiolabel binding assay. Oxazepam 2 was activated via its 3-chloro-1,4-benzodiazepine intermediate 3 and was reacted with a large series of aliphatic and aromatic amines. The substituted 3-anilino-1,4-benzodiazepine structure was identified as lead structure in a diverse series of 3-amino-1,4-benzodiazepines 4-38 and the full SAR (structure-activity relationship) optimisation provided 3-anilinobenzodiazepines 16-38 with CCK 1 receptor selectivity to CCK 2. The compounds 18, 24, 28 and 33 have shown affinities at the CCK 1 receptor of 11, 10, 11 and 9 nM, respectively. These equipotent CCK 1 ligands were fully evaluated in behaviour pharmacological essays. An antidepressant effect was identified in the tail suspension- and the Porsolt swimming-test. The ED 50 values for 24 and 28 were determined in these assays as 0.46 and 0.49 mg/kg. The mixed antagonist 37 showed in addition to the antidepressant effects anxiolytic properties. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Degradation, receptor binding, insulin secreting and antihyperglycaemic actions of palmitate-derivatised native and Ala8-substituted GLP-1 analogues

The hormone glucagon-like peptide-1(7-36)amide (GLP-1) is released in response to ingested nutrients and acts to promote glucose-dependent insulin secretion ensuring efficient postprandial glucose homeostasis. Unfortunately, the beneficial actions of GLP-1 which give this hormone many of the desirable properties of an antidiabetic drug are short lived due to degradation by dipeptidylpeptidase IV (DPP IV) and rapid clearance by renal filtration. In this study we have attempted to extend GLP-1 action through the attachment of palmitoyl moieties to the E-amino group in the side chain of the LyS26 residue and to combine this modification with substitutions of the Ala 8 residue, namely Val or amino-butyric acid (Abu). In contrast to native GLP-1, which was rapidly degraded, [Lys(pal) 26]GLP-1, [Abu8,Lys(pal)26]GLP-1 and [Val8,Lys-(pal)26]GLP-1 all exhibited profound stability during 12 h incubations with DPP IV and human plasma. Receptor binding affinity and the ability to increase cyclic AMP in the clonal β-cell line BRIN-BD11 were decreased by 86- to 167-fold and 15- to 62-fold, respectively compared with native GLP-1. However, insulin secretory potency tested using BRIN-BD11 cells was similar, or in the case of [Val8,Lys(pal)26]GLP-1 enhanced. Furthermore, when administered in vivo together with glucose to diabetic (ob/ob) mice, [Lys(pal)26]GLP-1, [Abu8,Lys(pal) 26]GLP-1 and [Val8,Lys(pal) 26]GLP-1 did not demonstrate acute glucose-lowering or insulinotropic activity as observed with native GLP-1. These studies support the potential usefulness of fatty acid linked analogues of GLP-1 but indicate the importance of chain length for peptide kinetics and bioavailability. Copyright © by Walter de Gruyter.

Novel 5-HT7 ligands as antidepressants:automated synthesis of N-substituted-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]-arylsulfon amides

The 5-HT7 receptor is linked with various CNS disorders. Using an automated solution phase synthesis a combinatorial library of 384 N-substituted N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]-arylsulfonamides was prepared with 24 chemically diverse amines 1-24 and 16 sulfonyl chlorides A-P. The chemical library of alkylated sulfonamides was evaluated in a receptor binding assay with [3]H-5-CT as ligand. The key synthetic step was the alkylation of a sulfonamide with iodide E, which was prepared from butanediol in 4 synthetic steps. The target compounds 1A, 1B .....24A ... 24P were purified by solvent extraction on a Teacan liquid handling system. Sulfonamide J20, B23, D23, G23, G23, J23 , I24 and O24 displayed a binding affinity IC50 between 100 nM and 10 nM. The crystalline J20 (IC50=39 nM) and O24 (IC50=83 nM) were evaluated further in the despair swimming test and the tail suspension assay. A significant antidepressant activity was found in mice of a greater magnitude than imipramine and fluoxetine at low doses. © 2006 Bentham Science Publishers Ltd.

Functionally Countable Spaces and Baire Functions

The concept of the distinguished sets is applied to the investigation of the functionally countable spaces. It is proved that every Baire function on a functionally countable space has a countable image. This is a positive answer to a question of R. Levy and W. D. Rice.

Piezoelectric and dielectric properties of Ce substituted La2Ti2O7 ceramics

The ferroelectric and dielectric properties of cerium (Ce) substituted La2Ti2O7 (LTO) have been investigated. Single phase, dense La2-xCexTi2O7 (x=0.15, 0.25, 0.35) ceramics were prepared by spark plasma sintering. The solubility limit of Ce in La2-xCexTi2O7 was found to be between 0.35 and 0.5. The a-, b- and c-axes of the unit cell decrease with increasing Ce substitution. The Curie point (Tc) of La2-xCexTi2O7 (x=0, 0.15, 0.25, 0.35) decreases and dielectric constant and loss increase with increasing Ce substitution. Cerium can increase the d33 of La2Ti2O7. The highest d33 was 3.9±0.1pC/N for La1.85Ce0.15Ti2O7 textured ceramic. © 2012 Elsevier Ltd.

Cholecystokinin-1 receptor antagonists:5-hydroxy-5-aryl-pyrrol-2-ones as anticancer agents

A new class of 5-arylated 5-hydroxypyrrolones was derived from mucochloric acid in 2 synthetic steps and the chemical structure was confirmed additionally by X-ray analysis. Using a radiolabelled binding assay, potent CCK1 selective ligands were identified (CCK1: 12 nM) and the antagonism was confirmed by using isolated tissue preparations. A series of isobutyl derivatives displayed unsurmountable CCK antagonistic properties and in vitro excellent inhibition of proliferation was obtained in cholecystokinin related cancer cell lines in the nanomolar range. Finally, using xenograft studies in nude mice, two selected pyrrolone derivatives, X = H and X = F a fluorinated analogue (PNB-028), showed a strong inhibition of tumour growth in a chemo-resistant colon cancer-(MAC 16) and a human pancreatic cell line (MIAPACA) at 50 mg kg-1 by oral administration.

Antidepressant/anxiolytic and anti-nociceptive effects of novel 2-substituted 1,4-benzodiazepine-2-ones

Oxazepam (4a) has been used as overall starting material in the synthesis of novel 2-substituted 1,4-benzodiazepines. By reacting Oxazepam 4a with commercially available hydrazines, hydrazides, semicarbazide, aminoguanidine and N,N-dimethylamino aniline in ethanol under acetic conditions, a series of diazenyl-1,4-benzodiazepines 5a-5i and 2-amino- 1,4-benzodiazepine 5k were obtained in good yields. These novel compounds served as new chemical entities (NCE) for testing in mice. The diazo-benzodiazepine 5d has shown a promising antidepressant effect in initial experiments in vivo at a dose of 5 mg/kg. The highly coloured 2-aminobenzodiazepine derivative 5k showed over a dose range from 5-50 mg/kg an analgesic effect in mice. © Singh et al.

I.~Synthesis, isolation, and characterization of 1-(2-anthryl)-2-cyclopropylethylene and 1-(2-naphthyl)-2-cyclopropylethylene. II.~Titanium dioxide photocatalysis of haloethers: A mechanistic study

I. The target molecules are classified as 1-aryl 2-cyclopropyl substituted ethylene. In the ground state, these molecules have a number of conformers, which are in equilibrium through rotation about single bonds. Once excited, the conformers have fixed conformation and are no longer in equilibrium and can be distinguished by their UV-vis as well as fluorescence spectra. The synthetic strategy involves standard steps. Both 2-methylanthracene and 2-methylnaphthalene were brominated using N-bromosuccinimide to give the bromomethyl adduct, which then was reacted with triphenylphosphine to form the phosphonium salt. This was followed by the formation of the phosphorus ylide, which upon treatment with cyclopropanecarboxaldehyde gave the product.^ II. The degradation of three aliphatic haloethers: bis-(2-chloroethyl) ether, bis-(2-chloroisopropyl) ether, and bis-(2-chloroethoxy)methane and two aromatic haloethers: 4-chlorodiphenyl ether and 4-bromodiphenyl ether was studied. Product studies have been conducted on the titanium dioxide photocatalysis of these compounds including mass balance, monitoring and identifying intermediates to establish the reaction pathways to deduce a mechanism for their degradation. The extent of mineralization was determined from the measurement of halogen anion (Cl$\sp-$/Br$\sp-$) as well as total organic carbon. The relative rates of disappearance of the individual haloethers appear to be related to the hydrophobic character of the given compound. Reaction mechanisms involving hydroxyl radical are proposed to explain the observed results. ^

Synthesis and characterization of photochromic indolyl substituted fulgides and fulgimides

The fulgide and fulgimide family constitutes an important class of organic photochromic compounds. The ability of fulgides and fulgimides to interconvert between two key forms by irradiation of different wavelength of light has made them promising material in optical memory devices, optical switches and sensors, and specialty dyes and inks. Thermal stability and hydrolytic stability of fulgides and fulgimides are essential for their practical applications. A deuterated trifluoromethyl indolylfulgide was synthesized based on the synthetic pathway of the proteo trifluoromethyl indolylfulgide using commercially available deuterated starting materials. Deuteration of the isopropylidene group improved the thermal stability of the indolylfulgide by a factor of 7. ^ Fulgimides are the most important fulgide derivatives. Fulgimides improve the hydrolytic stability of fulgides by replacing the succinic anhydride ring with a succinimide ring. A novel trifluoromethyl N-ethoxycarbonylmethyl indolylfulgimide was synthesized from trifluoromethyl indolylfulgide. The trifluoromethyl indolylfulgide was synthesized on a large scale in five steps with an overall yield of 18%. The indolylfulgide was then converted to indolylfulgimide by aminolysis follow by dehydration. The N-ethoxycarbonylmethyl indolylfulgimide showed enhanced hydrolytic stability and photochemical stability in 70/30 ethanol/water. ^ Three novel aqueous soluble fulgimides, trifluoromethyl carboxylic acid indolylfulgimide, dicarboxylic acid indolylfulgimide, and H-carboxylic acid indolylfulgimide, were synthesized. In sodium phosphate buffer (pH 7.4) at 37 ºC, an unusual hydrolysis of the trifluoromethyl group of the closed form of the carboxylic acid indolylfulgimide resulted in the dicarboxylic acid indolylfulgimide which has an additional carboxylic acid group. The closed form of dicarboxylic acid indolylfulgimide was further decarboxylated to generate H-carboxylic acid indolylfulgimide which was not photochromic. The trifluoromethyl dicarboxylic acid indolylfulgimide is the most robust fulgimide yet reported in aqueous solution. ^ A novel aqueous soluble methyl carboxylic acid indolylfulgimide was synthesized from methyl indolylfulgide. The methyl indolylfulgide was synthesized in five steps with an overall yield of 21%. The methyl carboxylic acid indolylfulgimide was synthesized by aminolysis follow by dehydration. The methyl carboxylic acid indolylfulgimide is expected to have improved thermal and photochemical stability in aqueous solutions relative to the trifluoromethyl analog.^