Urease inhibitory activity of simple alpha,beta-unsaturated ketones

A variety of alpha,beta-unsaturated ketones were evaluated for their effect on the jack bean urease. Of 35 compounds tested, 2-cyclohepten-1-one (1), 2-cyclohexen-1-one (2), 2-cyclopenten-1-one (3), and 5,6-dihydro-2H-pyran-2-one (4) showed potent inhibitory activities against the enzyme. The most potent compound (1) (IC50=0.16 mM) showed similar inhibitory potency to hydroxyurea (IC50=0.095 mM). The inhibitory effects of 1, 2, 3, and 4 were significantly reduced by 2-mercaptoethanol or dithiothreitol. These data suggest that alpha,beta-unsaturated ketones inhibited the urease activity, possibly by a Michael-like addition of a protein SH group to the double bond of the alpha,beta-unsaturated carbonyl group.     

Asymmetric catalysis with self-organized chiral lanthanum complexes: practical and highly enantioselective epoxidation of alpha,beta-unsaturated ketones

A highly efficient and practical method for obtaining alpha,beta-epoxy ketones with high optical purities was developed. The chiral lanthanum complex self-organized in situ from lanthanum triisopropoxide, (R)-BINOL, triarylphosphine oxide, and alkyl hydroperoxide (1:1:1:1) was found to catalyze the epoxidation of alpha,beta-unsaturated ketones with tert-butyl hydroperoxide or cumene hydroperoxide at room temperature to give the corresponding epoxy ketones in high enantioselectivities (up to >99% enantiomeric excess (ee)). A remarkably high asymmetric amplification, a positive nonlinear effect, was observed in the epoxidation of chalcone, which strongly suggests the formation of a dinuclear peroxide-involved mu-complex as the active catalyst.     

The role of alcohols as solvents in the genotoxicity testing of alpha,beta-unsaturated ketones in the SOS chromotest

alpha,beta-Unsaturated ketones are bifunctional compounds which form promutagenic 1,N(2)-propanodeoxyguanosine adducts like carcinogenic alpha,beta-unsaturated aldehydes and are mutagenic and genotoxic like these aldehydes. They are important industrial chemicals, are found in our environment and are widespread in our food. We investigated the SOS repair inducing activities of five ketones in the SOS chromotest and compared these results with that of the Ames test. Alkyl substitution at the beta-position of the alpha, beta-unsaturated carbonyl moiety leads to a decrease or loss in genotoxicity. Genotoxicity is higher if using ethanol as solvent instead of dimethylsulfoxide (DMSO). An increasing effect is also observed with methanol and n-propanol. Addition of the alcohol dehydrogenase inhibitor 4-methylpyrazole does not significantly influence the genotoxicity indicating that it is unlikely that the solvent effect depends on competitive inhibition of alcohol dehydrogenase by the alcohols used as solvents. Since other possible explanations e.g. ketal formation or solubility effects are also unlikely, the mechanism of this solvent effect observed with three different E. coli PQ-strains remains unresolved. No significant difference in genotoxicity of ethyl vinyl ketone was found between the strains PQ 37 and PQ 243 indicating that base excision repair does not play a role in the repair of 1,N(2)-propanodeoxyguanosine adducts, the main adducts of the alpha,beta-unsaturated ketones.     

Polyamino acids as catalysts in asymmetric synthesis

The use of polyamino acids in asymmetric organic synthesis is reviewed. Particular emphasis is placed on the asymmetric epoxidation of alpha,beta-unsaturated ketones with hydrogen peroxide in the presence of polyalanine or polyleucine, and further transformations of the epoxide products.     

Manganese (IV) oxide-catalyzed electrophilic diamination of electron-deficient alkenes provides an easy synthesis of alpha,beta-diamino acid and ketone derivatives for peptidomimetic studies.

Manganese (IV) oxide was found to catalyze the diamination reaction of alpha,beta-unsaturated esters and ketones with N,N-dichloro-p-toluenesulfonamide and acetonitrile as the halogen and nitrogen sources. The reaction is convenient to be conducted by simply mixing three reactants in the presence of manganese dioxide catalyst and 4 A molecular sieves, and provides an easy access to 1-p-toluenesulfonyl-3-trichloromethyl-4,5-imidazoline derivatives, which are useful building blocks for peptidomimetic studies.     

PaaSiCats: novel polyamino acid catalysts

The abilities of five polyamino acids (Paa's) to catalyse the asymmetric epoxidation of enones 1-7 under three sets of reaction conditions were compared: polyneo-pentylglycine and polyleucine showed distinct advantages in most circumstances. All five polymers were adsorbed onto silica and from this further study, immobilised polyneo-pentylglycine (PLNSi) and polyleucine (PLLSi) were shown to be the catalysts of choice for the asymmetric epoxidation of less-reactive alpha,beta-unsaturated ketones.     

Symmetric building blocks and combinatorial functional group transformation as versatile strategies in combinatorial chemistry

A combination of symmetric building blocks and combinatorial functional group transformation for synthesis of pyrimidines was investigated. The purpose of the study was to maximize the return on invested synthetic efforts of reaction development for libraries. A representative set of symmetric diacids was coupled onto deprotected TentaGel Rink Amide resin. The amino function served as a model of a chemical process providing a functional group for additional synthetic steps, while the symmetric building blocks served as a model to connect synthesis protocols and to switch to a different synthesis paradigm consecutively. The reaction sequence was continued in a noncombinatorial step by coupling a bifunctional reagent (3-aminoacetophenone) to the remaining carboxy function of the symmetric diacid. The ketone served as a model of a reagent prepared for combinatorial functional group transformation. The arylmethylketone was reacted with a set of aryl- and heteroarylaldehydes to give alpha,beta-unsaturated ketones. Subsequently, guanidine, alkyl-, and arylcarboxamidines were introduced in combinatorial synthesis of substituted pyrimidines by reaction with the alpha, beta-unsaturated ketone functionality. The combination of symmetric building blocks and combinatorial functional group transformation created a versatile reaction sequence ideally suited for production of libraries from libraries with added diversity.     

Syntheses and ultraviolet absorption of aza-steroids.

A series of aza-steroids was synthesized containing chromophoric groups, such as a, beta-unsaturated ketones and doubly unsaturated conjugated and monoconjugated heteroannular dienones with the heteroatom in the D ring at the 20 and 17a positions. The effect of an appositely placed electronegative center in these molecules upon their ultraviolet absorptions was studied. In order to obtain a basis for the observed spectral changes, the corresponding carbocyclic compounds were also synthesized. The maximum absorptions of the aza-steroids were hypsochromically shifted relative to the carbocyclic compounds in all cases (n=8). The displacement caused by the electronegative center on absorption maximum of the chromophores is, however, highly dependent on its location within the molecules.     

Oligopeptides as catalysts for asymmetric epoxidation

Oligopeptides are versatile catalysts for the enantioselective epoxidation of electron deficient alkenes, (e.g. alpha,beta-unsaturated ketones) with alkaline hydrogen peroxide. This review describes optimisation of the catalyst, substrate range, synthetic applications of the products and rationalisation of the stereoselectivity by an active site model.     

Axially dissymmetric N-thioacylated (S)-(-)-1,1'-binaphthyl-2,2'-diamine ligands for copper-catalyzed asymmetric Michael addition of diethylzinc to alpha,beta-unsaturated ketone

Axially chiral thioamide ligands L5, L6, L8, L11, and bis(thioamide) ligand L13 were prepared from the reaction of (S)-(-)-1,1'-binaphthyl-2,2'-diamine with acyl chlorides and phosphorus pentasulfide (P2S5). The catalytic asymmetric 1,4-addition of diethylzinc to alpha,beta-unsaturated ketones was examined using this novel chiral ligand system with 28-73% ee in moderate to good yields.     

Lewis acid-promoted transformation of 2-alkoxypyridines into 2-aminopyridines and their antibacterial activity. Part 2: Remarkably facile C-N bond formation

2-Alkoxy-3-cyano-4,6-diarylpyridines 1a,b which were synthesized by condensation of alpha,beta-unsaturated ketones with malononitrils were subjected to Lewis acid-catalyzed nucleophilic displacement reaction with various amines to afford the corresponding 2-aminopyridines 3-21. The potency of the results as antibacterial agents has been evaluated. The structure of the newly prepared compounds was assessed by microanalysis, IR, and NMR spectra. Molecular modeling and QSAR methods are used to study the antibacterial activity of the active compounds by means of the molecular mechanic method.     

Steroid transformations with Exophiala jeanselmei var. lecanii-corni and Ceratocystis paradoxa

The fungi Exophiala jeanselmei var. lecanii-corni [IMI (International Mycological Institute) 312989, UAMH (University of Alberta Microfungus Collection and Herbarium) 8783] and Ceratocystis paradoxa (IMI 374529, UAMH 8784) have been examined for their potential in steroid biotransformation. The study has determined that E. jeanselmei var. lecanii-corni effected overall anti-Markovnikov hydration on dehydroisoandrosterone, and side-chain degradation on a variety of pregnanes. Both ascomycetes were found to carry out redox reactions of alcohols and ketones as well as 1,4 reduction of alpha,beta-unsaturated carbonyl systems.     

Solid-phase synthesis and biological evaluation of a parallel library of 2,3-dihydro-1,5-benzothiazepines

Solid-phase synthesis of a parallel library of 3'-hydroxy-2,3-dihydrobenzothiazepines has been carried out through [4+3] annulation of alpha,beta-unsaturated ketones with aminothiophenol, using Wang resin as solid support. The synthesized compounds were evaluated for their potential as antibacterial, tumor inhibitors as well as acetyl- and butyrylcholinesterase inhibitors. None of the compounds showed any significant antibacterial activity. However, quite a few compounds showed significant potential as crown gall tumor inhibitors. These results reflect a strong exploratory potential in search of new benzothiazepines as source of anticancer agents. The results of the inhibition of cholinesterase revealed that benzothiazepines have a greater potential as butyrylcholinesterase inhibitors as compared to acetylcholinesterase. Moreover, the substitution of hydroxy group at C-3 in ring A led to increased activity when compared to unsubstituted- and 2'-OH substituted benzothiazepines.     

Diaryl-dialkyl-substituted pyrazoles: regioselective synthesis and binding affinity for the estrogen receptor

We have developed two novel series of tetrasubstituted pyrazoles, embodying 1,3-diaryl-4,5-dialkyl or 3,5-diaryl-1,4-dialkyl substitution patterns. The scope of a regioselective method, developed by us earlier, was expanded to allow the synthesis of the first series of these tetrasubstituted pyrazoles directly from alpha,beta-unsaturated ketones. The binding affinity of some of these pyrazoles for the estrogen receptor (ER) subtypes ERalpha and ERbeta is very high, and the overall affinity pattern suggests the importance of three phenol substituents for high affinity, ERalpha-selective binding.     

Synthesis, antimicrobial activity and conformational analysis of novel substituted pyridines: BF(3)-promoted reaction of hydrazine with 2-alkoxy pyridines

Some new 2-alkoxy-3-cyano-4,6-diarylpyridines 3,4 were synthesized by condensation of different alpha,beta-unsaturated ketones 1 with malononitrile 2, followed by cyclization in sodium alkoxide/alcohol system. Lewis acid-catalyzed reaction of 4 with hydrazine afforded the corresponding 1H-pyrazolo[3,4-b]pyridines 5. The potency of the results as antimicrobial agents has been evaluated. The structure of the newly prepared compounds was assessed by microanalysis, IR and NMR spectra. Molecular mechanics (MM2) and semiemperical (AM1) molecular orbital calculations have been performed for the most biologically active compounds 5b and c to get insight into their molecular structures and to learn more about their stable molecular conformations.     

Factors that affect the type of cell death induced by chemicals

Surveying about 1000 compounds, we found that several low molecular weight alpha, beta-unsaturated ketones induced non-apoptotic cell death characterized by the formation of autophagosomes, occasionally accompanied by mitochondrial shrinkage. The cytotoxic activity of these compounds was significantly reduced by the addition of N-acetyl-L-cysteine, suggesting their interaction with SH groups of intracellular targeted molecules (the so-called "non-sterically hindered Michael acceptor"). This suggests that the nature of the chemical structure as well as the type of target cells is another factor that determines the type of cell death induced by chemicals.     

The catalytic and kinetic mechanisms of NADPH-dependent alkenal/one oxidoreductase

NADPH-dependent alkenal/one oxidoreductase (AOR) from the rat is a phase 2/antioxidative enzyme that is known to catalyze the reduction of the carbon-carbon double bond of alpha,beta-unsaturated aldehydes and ketones. It is also known for its leukotriene B(4) 12-hydroxydehydrogenase activity. In order to begin to understand these dual catalytic activities and validate its classification as a reductase of the medium-chain dehydrogenase/reductase family, an investigation of the mechanism of its NADPH-dependent activity was undertaken. Recombinant AOR and a 3-nonen-2-one substrate were used to perform steady-state initial velocity, product inhibition, and dead end inhibition experiments, which elucidated an ordered Theorell-Chance kinetic mechanism with NADPH binding first and NADP(+) leaving last. A nearly 20-fold preference for NADPH over NADH was also observed. The dependence of kinetic parameters V and V/K on pH suggests the involvement of a general acid with a pK of 9.2. NADPH isomers stereospecifically labeled with deuterium at the 4-position were used to determine that AOR catalyzes the transfer of the pro-R hydride to the beta-carbon of an alpha,beta-unsaturated ketone, illudin M. Two-dimensional nuclear Overhauser effect NMR spectra demonstrate that this atom becomes the R-hydrogen at this position on the metabolite. Using [4R-(2)H]NADPH, small primary kinetic isotope effects of 1.16 and 1.73 for V and V/K, respectively, were observed and suggest that hydride transfer is not rate-limiting. Atomic absorption spectroscopy indicated an absence of Zn(2+) from active preparations of AOR. Thus, AOR fits predictions made for medium-chain reductases and bears similar characteristics to well known medium-chain alcohol dehydrogenases.     

Enhancing the in vitro and in vivo detection of aneuploidy by fluorescence in situ hybridization with the use of bromodeoxyuridine as a proliferation marker

alpha,beta-Unsaturated aldehydes are ubiquitous environmental pollutants, important industrial chemicals, have mani-fold biological functions in plants and insects and are natural products in food. They are endogenously formed in animals and humans during lipid peroxidation and arachidonic acid oxidation and are genotoxic, mutagenic and carcinogenic. Crotonaldehyde and 2-hexenal in food may contribute to general carcinogenicity in humans. The high bacterial toxicity of these compounds leads to problems in genotoxicity testing in bacterial systems. Recently, we have shown that using ethanol as solvent instead of dimethylsulfoxide (DMSO) results in an increase in the induction factors and the SOS-inducing potency of alpha,beta-unsaturated ketones in the SOS chromotest. Here, we demonstrate that utilization of ethanol as solvent also improves the testing of alpha,beta-unsaturated aldehydes. Five aldehydes out of nine tested were clearly positive in the SOS chromotest according to the criteria of Quillardet, i.e. acrolein, crotonaldehyde, 2,4-hexadienal, 2-methylacrolein and 2-ethylacrolein, three further, 2-hexenal, 2-heptenal and 2-propylacrolein showed a dose dependent increase of the induction factors which was however lower than 1.5 times that of the background. Only 2-butylacrolein did not lead to an increase in the induction factors. With DMSO as solvent only the three aldehydes acrolein, crotonaldehyde and 2,4-hexadienal showed an increase in the induction factor, which was however lower than 1.5 that of the background. Utilization of ethanol allows to establish structure genotoxicity relationships for alpha,beta-unsaturated aldehydes in the SOS chromotest. Genotoxicity decreases with increasing degree of substitution. The decreasing genotoxicities can be explained (a) by increasing bacterial toxicity due to increasing lipophilicities of the higher substituted aldehydes and (b) by decreasing reactivity due to steric hindrance by the alkyl substituents.     

Sugars containing alpha,beta-unsaturated carbonyl systems: synthesis and their usefulness as scaffolds in carbohydrate chemistry

The alpha,beta-unsaturated carbonyl function occurs in a wide variety of bioactive natural products. It is usually associated with the bioactivities of these compounds and acts as Michael acceptors for the addition of protein nucleophilic groups. The design and synthesis of sugars containing this functionality has provided a wide range of compounds, which can serve as building blocks of high synthetic versatility. This review deals with the chemistry of sugar-based molecules bearing singly linked or fused unsaturated lactones and ketones along with that of pyranoid enones and enonolactones. Examples are given of their syntheses and transformations into a variety of complex sugar derivatives such as branched-chain sugars, C-nucleosides, C-glycosyl derivatives, and various natural products, including selected analogues.