Construction of sulfur-containing compounds with anti-cancer stem cell activity using thioacrolein derived from garlic based on nature-inspired scaffolds.

Sulfur-containing compounds, such as cyclic compounds with a vinyl sulfane structure, exhibit a wide range of biological activities including anticancer activity. Therefore, the development of efficient strategies to synthesize such compounds is a remarkable achievement. We have developed a unique approach for the rapid and modular preparation of nature-inspired cyclic and acyclic sulfur-containing compounds using thioacrolein, a naturally occurring chemically unstable intermediate. We constructed thiopyranone derivatives through the regioselective sequential double Diels-Alder reaction of thioacrolein produced by allicin, a major component in garlic, and two molecules of silyl enol ether as the diene partner. The cytotoxicity toward cancer stem cells of the thiopyranones was equal to or higher than that of (Z)-ajoene (positive control) derived from garlic, and the thiopyranones had higher chemical stability than (Z)-ajoene.

Hypoxia and pH co-triggered oxidative stress amplifier for tumor therapy.

To keep fast proliferation, tumor cells are exposed to higher oxidative stress than normal cells and they upregulate the amount of some antioxidants such as glutathione (GSH) against reactive oxygen species to maintain the balance. This phenomenon is severe in hypoxic tumor cells. Although researchers have proposed a series of treatment strategies based on regulating the intracellular reactive oxygen species level, few of them are related to the hypoxic tumor. Herein, a novel organic compound (PLC) was designed by using lysine as a bridge to connect two functional small molecules, a hypoxia-responsive nitroimidazole derivative (pimonidazole) and a pH-responsive cinnamaldehyde (CA) derivative. Then, the oxidative stress amplifying ability of PLC in hypoxic tumor cells was evaluated. The acidic microenvironment of tumor can trigger the release of CA to produce reactive oxygen species. Meanwhile, large amount of nicotinamide adenine dinucleotide phosphate (NADPH) can be consumed to decrease the synthesis of GSH during the bio-reduction process of the nitro group in PLC under hypoxic conditions. Therefore, the lethal effect of CA can be amplified for the decrease of GSH. Our results prove that this strategy can significantly enhance the therapeutic effect of CA in the hypoxic tumor cells.

Application of Acrolein Imines to Organic Synthesis, Biofunctional Studies, and Clinical Practice.

N-alkyl unsaturated imines derived from acrolein, a toxin produced during oxidative stress, and biogenic alkyl amines occur naturally and are considered biologically relevant compounds. However, despite the recent conceptual and technological advances in organic synthesis, research on the new reactivity of these compounds is lacking. This personal account discusses research on the reactivity that has been overlooked in acrolein imines, including the discovery of new methods to synthesize biologically active compounds, the determination of new functions of relevant imines and their precursors, i. e., aldehydes and amines, and the application of these methods for clinical diagnosis.

Formulation, production, in vitro release and in vivo pharmacokinetics of cinnamaldehyde sub-micron emulsions.

Objective: The purpose of this study was to study the effects of formulation of cinnamaldehyde submicron emulsion (CA-SME) and optimize the preparation process parameters of CA-SME, characterize CA-SME and study on in vitro release kinetics and in vivo pharmacokinetics.Methods: Single factor methodology was used to screen the formulation of CA-SME. Response surface methodology combined with Box-Behnken design (BBD) was used to optimize the process variables of CA-SME. The dynamic dialysis method was used to investigate the in vitro release of CA from CA-SME. The blood concentrations of CA in rats were measured after oral administration of CA-SME, with CA solution as reference.Results: The optimal formulation of CA-SME was as follows: 2.5% CA + 1.5% Tween-80 and Span-80 (1:1)+1.5% medium chain triglyceride (MCT)+1.5% Poloxamer-188 + 1.5% lecithin + 91.5% ultrapure water. With the entrapment efficiency (EE/%) of CA-SME as index, BBD experiments indicated that the optimum emulsification temperature, homogenization pressure and cycles were 56 °C, 52 MPa, and two cycles, respectively. The mean particle size and EE of optimum CA-SME were 257.23 ± 3.74 nm and 80.31 ± 0.68%, respectively. The in vitro release study exhibited that the release kinetics of CA-SME was first-order model. Pharmacokinetic parameters of CA-SME in rats were Tmax 60 min, Cmax 1063.41 mg/L, AUC0-∞ 113102.61 mg/L*min, respectively. Tmax, Cmax, and AUC0-∞ of CA-SME were 3, 3.5, and 2.3 times higher than that of CA solution, respectively. The pharmacokinetic parameters of CA-SME in rats were significantly higher than those of CA solution. Submicron emulsion shows great potential as delivery strategy for this volatile herbal oil in oral administration.

In vitro antioxidant and in vivo antidepressant activity of green synthesized azomethine derivatives of cinnamaldehyde.

OBJECTIVES: In this study, three (CS-1 to CS-3) azomethine derivatives of cinnamaldehyde were green synthesized, characterized, and their antioxidant and antidepressant activities were explored. MATERIALS AND METHODS: The antioxidant effect of these compounds was initially performed in vitro using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay methods before subjecting them to in vivo experiments. Compounds showing potent antioxidant activity (CS-1 and CS-2) were investigated further for their antidepressant activity using the forced swim test (FST) and tail suspension test (TST). Ascorbic acid (AA) and fluoxetine (20 mg/kg, p.o) were used as reference drugs for comparison in the antioxidant and antidepressant experiments, respectively. RESULTS: It was observed that CS-2 and CS-3 exhibited highest DPPH (half maximal inhibitory concentration [IC50]: 16.22 and 25.18 µg/mL) and ABTS (IC50: 17.2 and 28.86 µg/mL) radical scavenging activity, respectively, compared to AA (IC50: 15.73 and 16.79 µg/mL) and therefore, both CS-2 and CS-3 were tested for their antidepressant effect using FST and TST as experimental models. Pretreatment of CS-2 and CS-3 (20 mg/kg) for 10 days considerably decreased the immobility time in both the FST and TST models. CONCLUSION: The antioxidant and antidepressant effect of CS-2 and CS-3 may be attributed to the presence of azomethine linkage in the molecule.

Influence of Catalyst Acid/Base Properties in Acrolein Production by Oxidative Coupling of Ethanol and Methanol.

Oxidative coupling of methanol and ethanol represents a new route to produce acrolein. In this work, the overall reaction was decoupled in two steps, the oxidation and the aldolization, by using two consecutive reactors to investigate the role of the acid/base properties of silica-supported oxide catalysts. The oxidation of a mixture of methanol and ethanol to formaldehyde and acetaldehyde was performed over a FeMoOx catalyst, and then the product mixture was transferred without intermediate separation to a second reactor, in which the aldol condensation and dehydration to acrolein were performed over the supported oxides. The impact of the acid/base properties on the selectivity towards acrolein was investigated under oxidizing conditions for the first time. The acid/base properties of the catalysts were investigated by NH3 -, SO2 -, and methanol-adsorption microcalorimetry. A MgO/SiO2 catalyst was the most active in acrolein production owing to an appropriate ratio of basic to acidic sites.

Cinnamaldehyde Analogues as Potential Therapeutic Agents.

Cinnamaldehyde analogues are a class of chemical substances originated from derivatization of cinnamaldehyde, and are structurally characterized by the presence of cinnamoyl moiety. Due to the presence of highly reactive α,α-unsaturated carbonyl pharmacophore (Michael acceptor) in their structures, these molecules are apt to react with some enzymes and/or receptors as electrophiles, and consequently produce diverse therapeutically relevant pharmacological functions. Naturally occurring molecules, trans-cinnamaldehyde (CA), 2-benzoyloxycinnam-aldehyde (2-BCA), and 2- hydroxycinnamaldehyde (2-HCA) are representatives of this group, and have attracted lots of interest for their bioactivities, especially the anti-cancer and anti-inflammatory properties. Owing to the potential of CA, 2-BCA, and 2-HCA as therapeutic agents, researches on chemical syntheses and modifications have been carried out to gain chemical entities with potent bioactivity and favorable druggability. This review summarizes the progress on phytochemical and pharmacological aspects of natural cinnamaldehyde analogues, illustrate the representative of synthetic molecules with potent bioactivity, and discuss their potential as therapeutic agents.

Design, synthesis and antibacterial activity of cinnamaldehyde derivatives as inhibitors of the bacterial cell division protein FtsZ.

In an attempt to discover potential antibacterial agents against the increasing bacterial resistance, novel cinnamaldehyde derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activity against nine significant pathogens using broth microdilution method, and their cell division inhibitory activity against four representative strains. In the in vitro antibacterial activity, the newly synthesized compounds generally displayed better efficacy against Staphylococcus aureus ATCC25923 than the others. In particular, compounds 3, 8 and 10 exerted superior or comparable activity to all the reference drugs. In the cell division inhibitory activity, all the compounds showed the same trend as their in vitro antibacterial activity, exhibiting better activity against S. aureus ATCC25923 than the other strains. Additionally, compounds 3, 6, 7 and 8 displayed potent cell division inhibitory activity with an MIC value of below 1 µg/mL, over 256-fold better than all the reference drugs.

A highly selective phenothiazine-based fluorescence 'turn-on' indicator based on cyanide-promoted novel protection/deprotection mechanism.

A cyanide anion (CN(-))-triggered deprotection of NH-protected phenothiazine, (E)-10-(10H-phenothiazin-3'-yl)propenal, has been discovered as a novel mechanism for the highly selective fluorescence detection of CN(-) under ambient conditions. The present protocol may pave the way for its broad application in organic synthesis in the near future.

Cu/Fe-cocatalyzed Meyer-Schuster-like rearrangement of propargylic amines: direct access to E-ß-aminoacryaldehydes.

A simple and efficient method for the synthesis of ß-aminoacryaldehydes via Cu(OAc)2·H2O and FeCl3 cocatalyzed Meyer-Schuster-Like rearrangement of propargylic amines was developed. The reactions proceed selectively as the E-isomers in generally good yields under aerobic conditions, and are compatible with a broad range of functional groups. This method combines C-N bond cleavage as well as the N-aryl group migration and provides a practical and mild synthetic approach to α,ß-unsaturated carbonyl compounds, which are useful precursors in a variety of functional group transformations.

Synthesis and antibacterial activity of cinnamaldehyde acylhydrazone with a 1,4-benzodioxan fragment as a novel class of potent ß-ketoacyl-acyl carrier protein synthase III (FabH) inhibitor.

Fatty acid biosynthesis is essential for bacterial survival. ß-Ketoacyl-acyl carrier protein (ACP) synthase III (FabH), is a particularly attractive antibacterial target, since it is central to the initiation of fatty acid biosynthesis. Three series of 21 cinnamaldehyde acylhydrazone derivatives, A3-9, B3-9, and C3-9, were synthesized and evaluated for FabH-inhibitory activity. Compound B6 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis (minimum inhibitory concentrations (MICs) values: 1.56-3.13 µg/mL) and was comparable with the positive control. Docking simulation by positioning compound B6 in the FabH structure active site was performed to explore the possible binding model.

Relationship between antimold activity and molecular structure of cinnamaldehyde analogues.

A quantitative structure-activity relationship (QSAR) modeling of the antimold activity of cinnamaldehyde analogues against of Aspergillus niger and Paecilomyces variotii was presented. The molecular descriptors of cinnamaldehyde analogues were calculated by the CODESSA program, and these descriptors were selected by best multi-linear regression method (BMLR). Satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii were obtained with R(2)=0.9099 and 0.9444, respectively. The models were also satisfactorily validated using internal validation and leave one out validation. The QSAR models provide the guidance for further synthetic work.

Induction of tumor cell death through targeting tubulin and evoking dysregulation of cell cycle regulatory proteins by multifunctional cinnamaldehydes.

Multifunctional trans-cinnamaldehyde (CA) and its analogs display anti-cancer properties, with 2-benzoyloxycinnamaldehyde (BCA) and 5-fluoro-2-hydroxycinnamaldehyde (FHCA) being identified as the ortho-substituted analogs that possess potent anti-tumor activities. In this study, BCA, FHCA and a novel analog 5-fluoro-2-benzoyloxycinnamaldehyde (FBCA), were demonstrated to decrease growth and colony formation of human colon-derived HCT 116 and mammary-derived MCF-7 carcinoma cells under non-adhesive conditions. The 2-benzoyloxy and 5-fluoro substituents rendered FBCA more potent than BCA and equipotent to FHCA. The cellular events by which these cinnamaldehydes caused G(2)/M phase arrest and halted proliferation of HCT 116 cells were thereby investigated. Lack of significant accumulation of mitosis marker phospho-histone H3 in cinnamaldehyde-treated cells indicated that the analogs arrested cells in G(2) phase. G(2) arrest was brought about partly by cinnamaldehyde-mediated depletion of cell cycle proteins involved in regulating G(2) to M transition and spindle assembly, namely cdk1, cdc25C, mad2, cdc20 and survivin. Cyclin B1 levels were found to be increased, which in the absence of active cdk1, would fail to drive cells into M phase. Concentrations of cinnamaldehydes that brought about dysregulation of levels of cell cycle proteins also caused tubulin aggregation, as evident from immunodetection of dose-dependent tubulin accumulation in the insoluble cell lysate fractions. In a cell-free system, reduced biotin-conjugated iodoacetamide (BIAM) labeling of tubulin protein pretreated with cinnamaldehydes was indicative of drug interaction with the sulfhydryl groups in tubulin. In conclusion, cinnamaldehydes treatment at proapoptotic concentrations caused tubulin aggregation and dysegulation of cell cycle regulatory proteins cdk1 and cdc25C that contributed at least in part to arresting cells at G(2) phase, resulting in apoptotic cell death characterized by emergence of cleaved forms of caspase 3 and poly (ADP-ribose) polymerase (PARP). Results presented in this study have thus provided further insights into the intricate network of cellular events by which cinnamaldehydes induce tumor cell death.

Solvent effects in ionic liquids: empirical linear energy-density relationships.

Multiparameter linear energy-density relationships to model solvent effects in room temperature ionic liquids (RTILs) are introduced and tested. The model incorporates two solvent dependent and two specific solute-solvent parameters represented by a set of electronic indexes derived from the conceptual density functional theory. The specific solute-solvent interactions are described in terms of the electronic chemical potential for proton migration between the anion or cation and the transition state structure of a specific reaction. These indexes provide a quantitative estimation of the hydrogen bond (HB) acceptor basicity and the hydrogen bond donor acidity of the ionic solvent, respectively. A sound quantitative scale of HB strength is thereby obtained. The solvent dependent contributions are described by the global electrophilicity of the cation and nucleophilicity of the anion forming the ionic liquid. The model is illustrated for the kinetics of cycloaddition of cyclopentadiene towards acrolein. In general, cation HB acidity outweighs the remaining parameters for this reaction.

Valorisation of glycerol as renewable feedstock: comparison of the exploration of chemical transformation methods aided by high throughput experimentation.

Renewable feedstocks have been in the spotlight of intensive research activities over the past 10 years. Glycerol is one of the feedstock molecules which has been the target of numerous research efforts, for a number of reasons. First of all glycerol is currently readily available due to the fact that it is a couple product of the first generation biodiesel production. Secondly glycerol can be taken as a representative model substrate to explore the options of selective conversion of sugar alcohols to products of value. In our paper we discuss potential routes for the valorisation of glycerol which lead to intermediates already established within the petrochemical value chain and illustrate what impact high throughput experimentation may have as a success factor on research and development for this field. As illustrative examples we have chosen the oxidative transformation of glycerol to acrolein and acrylic acid and the carbonylation of glycerol to C4-acids.

Oxazaborolidinium ion-catalyzed cyclopropanation of α-substituted acroleins: enantioselective synthesis of cyclopropanes bearing two chiral quaternary centers.

A catalytic synthetic route to highly functionalized chiral cyclopropane derivatives was developed by Michael-initiated cyclopropanation of α-substituted acroleins with aryl- and alkyl diazoacetates. In the presence of chiral (S)-oxazaborolidinium cation 1b as a catalyst, the reaction proceeded in high yield (up to 93%) with high to excellent diastereoselectivity (up to 98% de) and enantioselectivity (up to 95% ee).

Synthesis of functionalized cinnamaldehyde derivatives by an oxidative Heck reaction and their use as starting materials for preparation of Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase inhibitors.

Cinnamaldehyde derivatives were synthesized in good to excellent yields in one step by a mild and selective, base-free palladium(II)-catalyzed oxidative Heck reaction starting from acrolein and various arylboronic acids. Prepared α,ß-unsaturated aldehydes were used for synthesis of novel α-aryl substituted fosmidomycin analogues, which were evaluated for their inhibition of Mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate reductoisomerase. IC(50) values between 0.8 and 27.3 µM were measured. The best compound showed activity comparable to that of the most potent previously reported α-aryl substituted fosmidomycin-class inhibitor.

Radical dependence of the yields of methacrolein and methyl vinyl ketone from the OH-initiated oxidation of isoprene under NO(x)-free conditions.

Formation yields of methacrolein (MAC), methyl vinyl ketone (MVK), and 3-methyl furan (3MF) from the hydroxyl radical (OH) initiated oxidation of isoprene were investigated under NO(x)-free conditions (NO(x) = NO + NO(2)) at 50 °C and 1 atm in a quartz reaction chamber coupled to a mass spectrometer. Yields of the primary products were measured at various OH and hydroperoxy (HO(2)) radical concentrations and were found to decrease as the HO(2)-to-isoprene-based peroxy radical (ISORO(2)) concentration ratio increases. This is likely the result of a competition between ISORO(2) self- and cross-reactions that lead to the formation of the primary products, with reactions between these peroxy radicals and HO(2) which can lead to the formation of peroxides. Under conditions with HO(2)/ISORO(2) ratios close to 0.1, yields of MVK (15.5% ± 1.4%) and MAC (13.0% ± 1.2%) were higher than the yields of MVK (8.9% ± 0.9%) and MAC (10.9% ± 1.1%) measured under conditions with HO(2)/ISORO(2) ratios close to 1. This radical dependence of the yields was reproduced reasonably well by an explicit model of isoprene oxidation, suggesting that the model is able to reproduce the observed products yields under a realistic range of atmospheric HO(2)/ISORO(2) ratios.

Anticandidal activity of cinnamaldehyde, its ligand and Ni(II) complex: effect of increase in ring and side chain.

To increase efficacy of cinnamaldehyde as an antimycotic agent, N, N'- Bis (trans-cinnamadehyde) ethylenediimine [C(20)H(20)N(2)] and Ni(II) complex of the type [Ni(C(40)H(40)N(4))Cl(2)] have been synthesized. The ligand [P] and Ni(II) complex have been characterized on the basis of elemental analysis, FTIR, ESI- MS, IR, (1)H NMR, UV-Vis spectroscopic techniques, conductivity and magnetic measurements. MIC of cinnamaldehyde against clinical isolate of Candida albicans and Candida tropicalis was 400 microg/ml and 500 microg/ml, respectively. Synthesized ligand has markedly reduced MIC; 200 microg/ml and 300 microg/ml whereas Ni(II) complex of ligand displayed MIC of 90 microg/ml and 120 microg/ml. Growth and sensitivity of the organisms were effected by ligand & complex at significantly reduced concentration. Plasma membrane ATPase activity and ergosterol content have been investigated as site of action. Result obtained indicates ergosterol biosynthesis pathway as site of action of cinnamaldehyde, synthesized ligand and its Ni(II) complex.

Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention.

Trans-cinnamaldehyde (CA) and its analogs 2-hydroxycinnamaldehyde and 2-benzoyloxycinnamaldehyde have been reported to possess antitumor activity. CA is also a known Nrf2 activator. In this study, a series of ortho-substituted cinnamaldehyde analogs was synthesized and screened for antiproliferative and thioredoxin reductase (TrxR)-inhibitory activities. Whereas CA was weakly cytotoxic and TrxR inhibiting, hydroxy and benzoyloxy substitutions resulted in analogs with enhanced antiproliferative activity paralleling increased potency in TrxR inactivation. A novel analog, 5-fluoro-2-hydroxycinnamaldehyde, was identified as exhibiting the strongest antitumor effect (GI(50) 1.6 microM in HCT 116 cells) and TrxR inhibition (IC(50) 7 microM, 1 h incubation with recombinant TrxR). CA and its 2-hydroxy- and 2-benzoyloxy-substituted analogs possessed dual TrxR-inhibitory and Nrf2-inducing effects, both attributed to an active Michael acceptor pharmacophore. At lethal concentrations, TrxR-inhibitory potencies correlated with the compounds' antiproliferative activities. The penultimate C-terminal selenocysteine residue was shown to be a possible target. Conversely, at sublethal concentrations, these agents induced an adaptive antioxidant response through Nrf2-mediated upregulation of phase II enzymes, including TrxR induction. We conclude from the results obtained that TrxR inactivation contributes at least partly to cinnamaldehyde cytotoxicity. These Michael acceptor molecules can potentially be exploited for use in different concentrations in chemotherapeutic and chemopreventive strategies.