Synthesis, biological evaluation (antioxidant, antimicrobial, enzyme inhibition, and cytotoxic) and molecular docking study of hydroxy methoxy benzoin/benzil analogous.

In this work, due to the biological activity evaluation, a series of hydroxy methoxy benzoins (1-8), benzils (10-16) and methoxy benzoin/benzil-O-ß-d-glucosides (17-28) were synthesized. Antioxidant (FRAP, CUPRAC, DPPH), antimicrobial (16 microorganisms, and two yeast), enzyme inhibition (α-amylase, α-glucosidase, AChE, BChE, and tyrosinase) of all synthesized benzoin/benzil analogs were investigated. Benzoins (1-8) showed the most effective antioxidant properties compared to all three methods. Compound 28 against α-amylase, compound 9 against α-glucosidase, compound 11 against AChE, compound 2 against BChE, and compound 13 against tyrosinase showed the best activities with the better or similar IC50 values as used standards. Hydroxy methoxy benzoin compounds (1-8) among all four groups were seen as the most effective against the tested microorganism. Molecular docking analysis showed that all tested compounds 1-28 (0.01-2.22 µM) had the best binding affinity against AChE enzyme. Cytotoxic effects of the many of compounds (1-16, 21, and 24) also investigated and it was found that they caused different effects in different cells. The LDH tests of compounds 1a + b, 4, 7, 8, 9, 11, 12, 21, and 24, seemed to be effective compared to the positive control cisplatin. The cytotoxicity of compounds 6 (9.24%) for MCF7 cancer cells, 8 (5.16%) and 4 (8.26%) for HT29 cancer cells, 24 (9.84%) for Hep3B cells and 8 (8.52%), 7 (5.70%), 4 (6.94) and 9 (7.22%) for C6 cells were at normal values. And also cytotoxic activity of four compounds (5, 9, 21, and 24) among the all synthetic groups, were evaluated to the HeLa and RPE. Compound 5 showed anticancer activity on HeLa and RPE cancer cells as much as or better than cisplatin which was used as standard.

New antibacterial and 5-lipoxygenase activities of synthetic benzyl phenyl ketones: Biological and docking studies.

We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50) and kinetic assays of all the studied molecules (5 µg/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC50 = 3.5 µM; Ki = 4.8 µM) and 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-nitrophenyl)-ethanone (K206; IC50 = 2.3 µM; Ki = 0.7 µM) were potent, selective, competitive and nonredox inhibitors of 5-hLOX. Antioxidant behavior was also assayed by DPPH, FRAP, and assessing ROS production, and those with antibacterial and antiproliferative properties relating to 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-chlorophenyl)-ethanone (K208) established it as the most interesting and relevant compound studied, as it showed nearly 100% inhibition of bacterial growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Finally, docking studies were done that helped to characterize how the inhibitor structures correlated to decreased 5-hLOX activity.

Cu(II)-Catalyzed C-N Coupling of (Hetero)aryl Halides and N-Nucleophiles Promoted by α-Benzoin Oxime.

We first reported the new application of a translate metal chelating ligand α-benzoin oxime for improving Cu-catalyzed C-N coupling reactions. The system could catalyse coupling reactions of (hetero)aryl halides with a wide of nucleophiles (e.g., azoles, piperidine, pyrrolidine and amino acids) in moderate to excellent yields. The protocol allows rapid access to the most common scaffolds found in FDA-approved pharmaceuticals.

Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout.

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.

Sensitive spectrophotometric determination of Co(II) using dispersive liquid-liquid micro-extraction method in soil samples.

Analytical performance of conventional spectrophotometer was developed by coupling of effective dispersive liquid-liquid micro-extraction method with spectrophotometric determination for ultra-trace determination of cobalt. The method was based on the formation of Co(II)-alpha-benzoin oxime complex and its extraction using a dispersive liquid-liquid micro-extraction technique. During the present work, several important variables such as pH, ligand concentration, amount and type of dispersive, and extracting solvent were optimized. It was found that the crucial factor for the Co(II)-alpha benzoin oxime complex formation is the pH of the alkaline alcoholic medium. Under the optimized condition, the calibration graph was linear in the ranges of 1.0-110 µg L(-1) with the detection limit (S/N = 3) of 0.5 µg L(-1). The preconcentration operation of 25 mL of sample gave enhancement factor of 75. The proposed method was applied for determination of Co(II) in soil samples.

Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα).

The oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has made it an attractive target for anticancer drug design. In this work, we describe our efforts to optimize the lead PI3Kα inhibitor 2-hydroxy-1,2-diphenylethanone (benzoin). A series of 2-oxo-1,2-diphenylethyl benzoate analogs were identified as potential PI3Kα inhibitors. Docking studies confirmed that the aromatic interaction is mediating ligand/protein complex formation and identified Lys802 and Val851 as H-bonding key residues. Our biological data in human colon carcinoma HCT116 showed that the structure analogs inhibited cell proliferation and induced apoptosis.

Synthesis, immobilization and catalytic activity of a copper(II) complex with a chiral bis(oxazoline).

A chiral bis(oxazoline) bearing CH2OH groups was synthesized from a commercial bis(oxazoline) and characterized by 1H- and 13C-NMR, high resolution ESI-mass spectrometry and FTIR. The corresponding copper(II) complex was immobilized onto the surface of a mesoporous carbonaceous material (Starbon® 700) in which the double bonds had been activated via conventional bromination. The materials were characterized by elemental analysis, ICP-OES, XPS, thermogravimetry and nitrogen adsorption at 77 K. The new copper(II) bis(oxazoline) was tested both in the homogeneous phase and once immobilized onto a carbonaceous support for the kinetic resolution of hydrobenzoin. Both were active, enantioselective and selective in the mono-benzoylation of hydrobenzoin, but better enantioselectivities were obtained in the homogeneous phase. The heterogeneous catalyst could be separated from the reaction media at the end of the reaction and reused in another catalytic cycle, but with loss of product yield and enantioselectivity.

[Effect of (E)-2-(4-bromophenyl )-1-(3,4-dihydroxyphenyl )ethanone oxime on proliferation and activation of mice lymphocytes].

OBJECTIVE: To study the effects of (E)-2-(4-bromophenyl)-1-(3, 4-dihydroxyphenyl) ethanone oxime (BDEO) on the proliferation and activation of the mice' s splenic lymphocytes and the peripheral blood lymphocytes induced by Concanavalin A (Con A) in vitro and in vivo, and its molecular mechanism. METHODS: During the lymphocyte proliferation and activation induced by Con A in vitro, MTT and cell counting were used to detect the transformation rates and survival rates of lymphocytes, and ELISA was used to measure the activity of caspase-9; moreover, the levels of Bax, Bcl-2 and caspase-3 were determined by Western blot, in order to observe the effects of BDEO on cell proliferation and activation. The effects of administration of Con A [15 mg/(kg x d)] and BDEO [(3, 6 mg/(kg x d)] by intraperitoneal injection on transformation rates of spleen cells and peripheral blood lymphocyte, as well as phagocytosis rate of peritoneal macrophages in mice were also observed in vivo. RESULTS: 0.3-1 micromol/L BDEO significantly inhibited the transformation rates and growth of mice lymphocyte (P < 0.05). The activity of caspase-9 and the levels of mitochondrial pro-apoptotic protein Bax and Bak gradually increased, then decreased as the BDEO continually accumulated. Anti-apoptotic protein Bcl-2 as well as mitochondrial Cyt C levels first decreased then increased gradually, and cytoplasmic Cyt C, cleaved caspase-9 and cleaved caspase-3 levels showed firstly a increase, then decrease gradually. Additionally, administration of BDEO by intraperitoneal injection significantly inhibited proliferation of spleen lymphocytes and peripheral blood lymphocyte, as well as phagocytosis of peritoneal macrophagesin in mice. CONCLUSION: BDEO might regulate the proliferation and activation of lymphocytes through activation of caspase-3 mainly via a mitochondrial intrinsic pathway; the inhibiting effect on the proliferation and transformation rate of lymphocytes was significant when the concentration of BDEO was relatively low; as the concentration accumulated increasingly, the inhibiting effect reduced. The results indicated that BDEO has immunosuppressive activity.

Cytotoxic deoxybenzoins and diphenylethylenes from Arundina graminifolia.

Eight new C-4-alkylated deoxybenzoins (1-8), three new diphenylethylenes (9-11), and five known diphenylethylenes were isolated from Arundina graminifolia. The structures of 1-11 were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 9-11 are the first naturally occurring diphenylethylenes possessing a hydroxyethyl unit. Compounds 1-11 were evaluated for cytotoxicity against five human tumor cell lines. Compounds 4, 5, and 9-11 showed significant cytotoxicity against five cancer cell lines, with IC50 values ranging from 1.8 to 8.7 µM.

Photoremovable chiral auxiliary.

A new concept of a photoremovable chiral auxiliary (PCA), based on the chiral benzoin chromophore, is introduced. This moiety can control the asymmetric formation of a Diels-Alder adduct, and then be removed in a subsequent photochemical step in high chemical and quantum yields. Selective formation of the products at up to 96% ee was observed in the presence of a Lewis acid catalyst in the case of a 2-methoxybenzoinyl chiral auxiliary.

Design, synthesis and molecular simulation studies of dihydrostilbene derivatives as potent tyrosinase inhibitors.

The synthesis, molecular modeling and biological evaluation of substituted deoxybenzoins and optimized dihydrostilbenes are reported. Preliminary structure-activity relationship data were elucidated and lead compounds suitable for further optimization were discovered. Dihydrostilbene 7 is a particularly potent inhibitor (IC(50)=8.44 µM, more potent than kojic acid).

Molecular recognition and self-assembly special feature: A general protocol for creating high-throughput screening assays for reaction yield and enantiomeric excess applied to hydrobenzoin.

A general approach to high-throughput screening of enantiomeric excess (ee) and concentration was developed by using indicator displacement assays (IDAs), and the protocol was then applied to the vicinal diol hydrobenzoin. The method involves the sequential utilization of what we define herein as screening, training, and analysis plates. Several enantioselective boronic acid-based receptors were screened by using 96-well plates, both for their ability to discriminate the enantiomers of hydrobenzoin and to find their optimal pairing with indicators resulting in the largest optical responses. The best receptor/indicator combination was then used to train an artificial neural network to determine concentration and ee. To prove the practicality of the developed protocol, analysis plates were created containing true unknown samples of hydrobenzoin generated by established Sharpless asymmetric dihydroxylation reactions, and the best ligand was correctly identified.

Effects of Litchi chinensis fruit isolates on prostaglandin E(2) and nitric oxide production in J774 murine macrophage cells.

BACKGROUND: Litchi chinensis is regarded as one of the 'heating' fruits in China, which causes serious inflammation symptoms to people. METHODS: In the current study, the effects of isolates of litchi on prostaglandin E(2) (PGE(2)) and nitric oxide (NO) production in J774 murine macrophage cells were investigated. RESULTS: The AcOEt extract (EAE) of litchi was found effective on stimulating PGE(2) production, and three compounds, benzyl alcohol, hydrobenzoin and 5-hydroxymethyl-2-furfurolaldehyde (5-HMF), were isolated and identified from the EAE. Benzyl alcohol caused markedly increase in PGE(2) and NO production, compared with lipopolysaccharide (LPS) as positive control, and in a dose-dependent manner. Hydrobenzoin and 5-HMF were found in litchi for the first time, and both of them stimulated PGE(2) and NO production moderately in a dose-dependent manner. Besides, regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) mRNA expression and NF-κB (p50) activation might be involved in mechanism of the stimulative process. CONCLUSION: The study showed, some short molecular compounds in litchi play inflammatory effects on human.

Arylalkyl ketones, benzophenones, desoxybenzoins and chalcones inhibit TNF-α induced expression of ICAM-1: structure-activity analysis.

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in the pathogenesis of various inflammatory and autoimmune diseases. Small molecules that block these interactions have been targeted as potential therapeutic agents against acute and chronic inflammatory diseases. In an effort to identify potent intercellular cell adhesion molecule-1 (ICAM-1) inhibitors, a large number of arylalkyl ketones, benzophenones, desoxybenzoins and chalcones and their analogs (54 in total) have been synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity relationship studies of these compounds identified three potent chalcone derivatives and also demonstrated the possible mechanism for their ICAM-1 inhibitory activities. The most active compound was found to be 79.

Chiral micellar electrokinetic chromatography-atmospheric pressure photoionization of benzoin derivatives using mixed molecular micelles.

In the present work we report, for the first time, the successful on-line coupling of chiral MEKC (CMEKC) to atmospheric pressure photoionization MS (APPI-MS). Four structurally similar neutral test solutes (e.g. benzoin (BNZ) derivatives) were successfully ionized by APPI-MS. The mass spectra in the positive ion mode showed that the protonated molecular ions of BNZs are not the most abundant fragment ions. Simultaneous enantioseparation by CMEKC and on-line APPI-MS detection of four photoinitiators, hydrobenzoin, BNZ, benzoin methyl ether, benzoin ethyl ether, were achieved using an optimized molar ratio of mixed molecular micelle of two polymeric chiral surfactants (polysodium N-undecenoxy carbonyl-L-leucinate and polysodium N-undecenoyl-L,L-leucylvalinate). The CMEKC conditions, such as voltage, chiral polymeric surfactant concentration, buffer pH, and BGE concentration, were optimized using a multivariate central composite design (CCD). The sheath liquid composition (involving %v/v methanol, dopant concentration, electrolyte additive concentration, and flow rate) and spray chamber parameters (drying gas flow rate, drying gas temperature, and vaporizer temperature) were also optimized with CCD. Models built based on the CCD results and response surface method were used to analyze the interactions between factors and their effects on the responses. The final overall optimum conditions for CMEKC-APPI-MS were also predicted and found in agreement with the experimentally optimized parameters.

Asymmetric autocatalysis: triggered by chiral isotopomer arising from oxygen isotope substitution.

Trigger happy: chiral oxygen isotopomers of hydrobenzoin ([(18)O](R)-1 and [(18)O](S)-1) acted as chiral triggers to induce the enantioselective addition of iPr(2)Zn to pyrimidine-5-carbaldehyde. An extremely small chiral influence arising from the presence of the oxygen isotope ((18)O) is amplified through asymmetric autocatalysis to enantioenrich the 5-pyrimidyl alkanol product.

Design and synthesis of novel deoxybenzoin derivatives as FabH inhibitors and anti-inflammatory agents.

Beta-ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of new FabH inhibitors. The synthesis and biological evaluation halide-deoxybenzoins derivatives are described in this Letter. Potent FabH inhibitory and selective anti-Gram-negative bacteria activities were observed in deoxybenzoin derivatives. Furthermore, compound 19 was able to reduce the ECE-induced IL-8 production in gastric mucosal cells significantly. Based on the biological data and molecular docking, compound 19 is a potential FabH inhibitor and anti-inflammatory agent deserving further research.

Isolation of 2,4,4'-trihydroxydeoxybenzoin and 3'-hydroxydaidzein from soybean miso.

Two 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging compounds were isolated from soybean miso. They were determined to be 2,4,4'-trihydroxydeoxybenzoin and 3'-hydroxydaidzein on the basis of spectroscopic data. In the manufacturing process for soybean miso, 2,4,4'-trihydroxydeoxybenzoin appeared during culture aging, and the quantity of it increased in a time-dependent manner.

The reaction of singlet oxygen with enecarbamates: a mechanistic playground for investigating chemoselectivity, stereoselectivity, and vibratioselectivity of photooxidations.

Photochirogenesis, the control of chirality in photoreactions, is one of the most challenging problems in stereocontrolled photochemistry, in which the stereodifferentiation has to be imprinted within the short lifetime of the electronically excited state. Singlet oxygen (1O2), an electronically excited molecule that is known to be sensitive to vibrational deactivation, has been selected as a model case for testing stereoselective control by vibrational deactivation. The stereoselectivity in the reaction of 1O2 with E/Z enecarbamates 1, equipped with the oxazolidinone chiral auxiliary, has been examined for the mode selectivity ([2 + 2]-cycloaddition versus ene-reaction) and the stereoselectivity in the oxidative cleavage of the alkenyl functionality to the methyldesoxybenzoin (MDB) product. Through the appropriate choice of substituents in the enecarbamate, the mode selectivity (ene versus [2 + 2]), which depends on the alkene geometry (E or Z), the steric bulk of the oxazolidinone substituent at the C-4 position, and the C-3' configuration on the side chain, may be manipulated. Phenethyl substitution gives exclusively the [2 + 2]-cycloaddition product, irrespective of the alkene geometry. The stereoselection in the resulting methyldesoxybenzoin (MDB) product is examined in a variety of solvents as a function of temperature by using chiral GC analysis. The extent (% ee) as well as the sense (R versus S) of the stereoselectivity in the MDB formation for the E isomer depends significantly on solvent and temperature, whereas the corresponding Z isomers are not affected by such variations. The complex temperature and solvent effects are scrutinized in terms of the differential activation parameters (DeltaDeltaS++, DeltaDeltaH++) for the photooxygenation of E/Z-enecarbamates in various solvents at different temperatures. The enthalpy-entropy compensations provide a mechanistic understanding of the temperature dependence of the ee values for the MDB product and the difference in the behavior between the Z and E enecarbamates. The E enecarbamates show a relatively high contribution from the entropy term and an appreciable contribution from the enthalpy term; both terms possess the same sign. In contrast, the corresponding relative insensitivity of Z enecarbamates to temperature and solvent variation is convincingly explained by the near-zero DeltaDelta S++ and DeltaDelta H++. Such effects, associated with temperature- and solvent-dependent conformational factors, are most likely dictated by the stereogenic center at the C-3' phenethyl substituent. The high stereocontrol during the photooxygenation of the chiral enecarbamates is shown to be independent of the steric demand of the oxazolidinone substituent at the C-4 position. In view of the reduced stereocontrol on deuteration of the oxazolidinone substituent at the C-4 position, we propose that the unusual stereoselective vibrational quenching of the attacking singlet oxygen (excited-state reactivity), a novel mechanistic concept, works in concert with the usual steric impositions (ground-state reactivity) exercised by the substituents to afford the high stereoselectivity observed in the dioxetane product during the [2 + 2] cycloaddition. Such synergistic interplay is held responsible for the highly stereoselective photooxidative cleavage of the chiral enecarbamates. The efficacy of stereocontrol in this photooxidation is demonstrated by kinetically resolving the epimers of the enecarbamate cleavage product (MDB) in essentially perfect stereoselectivity, a new methodology that we coin "photo-Pasteur-type kinetic resolution".

Chiral cobalt-catalyzed enantiomer-differentiating oxidation of racemic benzoins by using molecular oxygen as stoichiometric oxidant.

An efficient enantioselective oxidative reaction catalyzed by a chiral cobalt complex has been developed by using molecular oxygen as the stoichiometric oxidant (see scheme). The very mild reaction conditions of the catalytic system provide access to a wide range of benzoins (alpha-hydroxyketones) in high yield and excellent enantioselectivity (s (k(f)/k(s)) up to 47). This method is very versatile because the sole by-product of our oxidation process is water, which makes our system more eco-friendly and green.