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 mixed amino acids complexes of iron(III) and zinc(II) with isonitrosoacetophenone: Synthesis, spectral characterization, DFT study and anticancer activity.

New mixed Fe(III) and Zn(II) complexes with isonitrosoacetophenone (HINAP) and l-amino acids (such as l-histidine, l-phenylalanine and l-proline) have been synthesized and characterized by elemental analyses, UV-Vis, IR and ESR spectroscopy and thermal analyses. The values of molar conductance of the complexes in DMSO solution at 10-3 M concentration indicate their non-electrolyte nature. IR spectroscopy has revealed the coordination of deprotonated ligands to metal through nitrogen and oxygen atoms in an N2O2 arrangement. Density functional theory (DFT) calculations were performed using the hybrid functional of Truhlar and Zhao (M06) with basis set of double zeta quality LANL2DZ to evaluate the cis and trans coordination modes and to ascertain dipole moment, HOMO-LUMO energy gap, chemical hardness, softness and electrophilicity. The magnetic moments and ESR measurements suggest that there is an admixture of S = 5/2 and S = 1/2 spins in Fe(III) complexes. UV-Visible spectra indicate a distorted octahedral geometry around the metal ions. Thermal analyses show the presence of hydrated and coordinated water. The antimicrobial activity was investigated against (G+ and G-) bacteria (Staphylococcus aureus, bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa) and fungi (Candida albicans). The iron and zinc complexes were found to be more active against Gram-positive than Gram negative bacteria. They also show considerable growth inhibition against the fungi tested. In vitro antitumor activity assayed against cancer cell lines of the HEP2 type (cancer cells of the larynx) exhibited significant toxicity of the ligands and their mixed complexes.

Development of a fluorescent probe for detection of citrulline based on photo-induced electron transfer.

Peptidyl arginine deiminases (PADs) catalyze the post-translational deimination of peptidyl arginine residues to form citrulline residues. Aberrant citrullination of histones by one of the PAD isozymes, PAD4, is associated with various diseases, including rheumatoid arthritis, so high-throughput screening systems are needed to identify PAD4 inhibitors as chemical tools to investigate the role of PAD4, and as candidate therapeutic agents. Here, we utilized the addition-cyclization reaction between phenylglyoxal and citrulline under acidic conditions to design turn-on fluorescent probes for citrulline based on the donor-excited photoinduced electron transfer (d-PeT) mechanism. Among several derivatives of phenylglyoxal bearing a fluorescent moiety, we found that FGME enabled detection of citrulline without a neutralization process, and we used it to establish a simple methodology for turn-on fluorescence detection of citrulline.

Synthesis of benzil-o-carboxylate derivatives and isocoumarins through neighboring ester-participating bromocyclizations of o-alkynylbenzoates.

Bromide mediated neighboring ester-participating bromocyclizations of o-alkynylbenzoates are described here for the synthesis of benzil-o-carboxylates. 4-bromoisocoumarins are also synthesized when phenyl o-alkynylbenzoate is used as the substrate. Mechanistic studies suggest that the whole process is composed of an electrophilic bromocyclization and a dibromohydration-based ring-opening, and the neighboring ester group participates in the bromocyclization. Interestingly, the two oxygen atoms of the keto carbonyls in benzil-o-carboxylates are both derived from water. The electrophilic bromo source is in situ generated from the oxidation of bromide.

Copper-catalyzed direct synthesis of diaryl 1,2-diketones from aryl iodides and propiolic acids.

Benzil derivatives such as diaryl 1,2-diketones are synthesized via the direct decarboxylative coupling reaction of aryl propiolic acids and their oxidation. The optimized conditions are that the reaction of aryl propiolic acids and aryl iodides is conducted at 140 °C for 6 h in the presence of 10 mol % CuI/Cu(OTf)2 and Cs2CO3, after which HI (aq) is added and further reacted. The method shows good functional group tolerance toward ester, aldehyde, cyano, and nitro groups. In addition, symmetrical diaryl 1,2-diketones are obtained from aryl iodides and propiolic acid in the presence of palladium and copper catalysts.

One-pot, two-step desymmetrization of symmetrical benzils catalyzed by the methylsulfinyl (dimsyl) anion.

An operationally simple one-pot, two-step procedure for the desymmetrization of benzils is herein described. This consists in the chemoselective cross-benzoin reaction of symmetrical benzils with aromatic aldehydes catalyzed by the methyl sulfinyl (dimsyl) anion, followed by microwave-assisted oxidation of the resulting benzoylated benzoins with nitrate, avoiding the costly isolation procedure. Both electron-withdrawing and electron-donating substituents may be accommodated on the aromatic rings of the final unsymmetrical benzil.

Practical approach for preparation of unsymmetric benzils from ß-ketoaldehydes.

An efficient and practical method for the synthesis of unsymmetric benzils from readily available ß-ketoaldehydes has been developed. Various unsymmetric 1,2-diaryldiketones bearing functional groups have been obtained in good to excellent yields under mild reaction conditions. A plausible mechanism was proposed, and α,α-dichloroketone was considered as the key intermediate. The generation of α,α-dichloroketones from ß-ketoaldehydes may undergo the following steps: (1) oxidation by sodium hypochlorite, (2) decarboxylation, and (3) chlorination by Cl2 generated from sodium hypochlorite.

Gold(III)-catalyzed three-component coupling reaction (TCC) selective toward furans.

An efficient three-component coupling reaction toward a variety of furan derivatives has been developed. This cascade transformation proceeds via the gold-catalyzed coupling reaction of phenylglyoxal derivatives, secondary amines, and terminal alkynes, under the reaction conditions, that undergoes cyclization into the furan core.

Unidirectional growth of benzil crystal from solution by Sankaranarayanan-Ramasamy method and its characterization.

Good quality <100> benzil single crystal with a diameter 18 mm and length 75 mm was successfully grown from solution by the unidirectional growth method of Sankaranarayanan-Ramasamy (SR) for the first time in the literature. The seed crystals have been harvested from conventional solution growth technique and subsequently used for unidirectional growth. The grown crystal was subjected to various characterization studies. The results of UV-vis spectral analysis, photoluminescence, etching and microhardness studies were compared with conventional solution grown crystal to that of SR method grown crystal. The quality of SR method grown benzil crystal is better than conventional solution grown crystal.

Gold-catalyzed synthesis of benzil derivatives and α-keto imides via oxidation of alkynes.

An efficient process based on the gold-catalyzed redox reaction has been developed to oxidize 1,2-diarylacetylene or ynamide to 1,2-diaryldiketone or α-keto imide respectively. This process can tolerate a variety of functional groups and affords 1,2-dicarbonyl compounds in excellent yields under mild reaction conditions.

An efficient oxidation of benzoins to benzils by ACC/silica gel under ultrasound irradiation.

The oxidation of benzoins to the corresponding benzils was carried out in CH2Cl2 by ACC/silica gel in excellent yields within short time under ultrasound irradiation.

Synthesis of unsymmetrical benzil licoagrodione.

A synthesis of unsymmetrical 1,2-diarylethane-1,2-dione is reported involving the intramolecular cyclization of anionic benzylic ester of the aryl benzyl ether followed by oxidation employing dioxirane. With the use of microwave irradiation, licoagrodione was prepared from Claisen rearrangement of the corresponding allyl phenyl ether 1,2-diketone readily available from the Lindlar's reduction of the corresponding alkyne derivative. Subsequent removal of protecting groups then furnished the desired product.

Synthesis and antitumor activity of benzils related to combretastatin A-4.

A series of benzil derivatives related to combretastatin A-4 (CA-4) have been synthesized by oxidation of diarylalkynes promoted by PdI(2) in DMSO. Using this new protocol, 14 benzils were prepared in good to excellent yields and their biological activity has been delineated. Several benzils exhibited excellent antiproliferative activity: for example, 4j and 4k bearing the greatest resemblance to CA-4 and AVE-8062, respectively, were found to inhibit cell growth at the nanomolar level (20-50nM) on four human tumor cell lines. Flow cytometric analysis indicates that these compounds act as antimitotics and arrest the cell cycle in G(2)/M phase. A cell-based assay indicated that compounds 4j and 4k displayed a similar inhibition of tubulin assembly with an IC(50) value similar to CA-4. These results clearly demonstrated that the Z-double bond of CA-4 can be replaced by a 1,2-diketone unit without significant loss of cytotoxicity and inhibition of tubulin assembly potency.

Synthesis, spectroscopic and thermal studies of transition metal complexes derived from benzil and diethylenetriamine.

A macrocyclic ligand, bdta (where bdta=3,6,9,12,15,18-hexaaza-1,2,10,11-tetraphenyl-2,9,11,18-tetraenecyclododecane) has been prepared by cyclocondensation of benzil with diethylenetriamine which efficiently encapsulates transition as well as pseudo-transition metal ions leading to the formation of M(bdta)Cl2 type complexes [where M=Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II)]. The analytical, spectroscopic and magnetic moment data suggests an octahedral geometry for all the complexes. EPR spectra of Mn(II) and Cu(II) show considerable exchange interaction in the complex. They are non-conducting in DMSO. The TGA profile of the ligand and its complexes are identical and consists of two discreet stages. The voltammogram of Cu-complex exhibits a quasi-reversible one-electron transfer wave for Cu(II)/Cu(I) couple.

Inhibition of carboxylesterases by benzil (diphenylethane-1,2-dione) and heterocyclic analogues is dependent upon the aromaticity of the ring and the flexibility of the dione moiety.

Benzil has been identified as a potent selective inhibitor of carboxylesterases (CEs). Essential components of the molecule required for inhibitory activity include the dione moiety and the benzene rings, and substitution within the rings affords increased selectivity toward CEs from different species. Replacement of the benzene rings with heterocyclic substituents increased the K(i) values for the compounds toward three mammalian CEs when using o-nitrophenyl acetate as a substrate. Logarithmic plots of the K(i) values versus the empirical resonance energy, the heat of union of formation energy, or the aromatic stabilization energy determined from molecular orbital calculations for the ring structures yielded linear relationships that allowed prediction of the efficacy of the diones toward CE inhibition. Using these data, we predicted that 2,2'-naphthil would be an excellent inhibitor of mammalian CEs. This was demonstrated to be correct with a K(i) value of 1 nM being observed for a rabbit liver CE. In addition, molecular simulations of the movement of the ring structures around the dione dihedral indicated that the ability of the compounds to inhibit CEs was due, in part, to rotational constraints enforced by the dione moiety. Overall, these studies identify subdomains within the aromatic ethane-1,2-diones, that are responsible for CE inhibition.

Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.

Carboxylesterases (CE) are ubiquitous enzymes responsible for the metabolism of xenobiotics. Because the structural and amino acid homology among esterases of different classes, the identification of selective inhibitors of these proteins has proved problematic. Using Telik's target-related affinity profiling (TRAP) technology, we have identified a class of compounds based on benzil (1,2-diphenylethane-1,2-dione) that are potent CE inhibitors, with K(i) values in the low nanomolar range. Benzil and 30 analogues demonstrated selective inhibition of CEs, with no inhibitory activity toward human acetylcholinesterase or butyrylcholinesterase. Analysis of structurally related compounds indicated that the ethane-1,2-dione moiety was essential for enzyme inhibition and that potency was dependent on the presence of, and substitution within, the benzene ring. 3D-QSAR analyses of these benzil analogues for three different mammalian CEs demonstrated excellent correlations of observed versus predicted K(i) (r(2) > 0.91), with cross-validation coefficients (q(2)) of 0.9. Overall, these results suggest that selective inhibitors of CEs with potential for use in clinical applications can be designed.

Synthesis and evaluation of 4-(3-methyl-2-butenoxy) isonitrosoacetophenone, a radiation-induced stress metabolite in Citrus.

The time- and dose-dependent occurrence of 4-(3-methyl-2-butenoxy)isonitrosoacetophenone, a gamma-irradiation-induced stress metabolite was investigated. The chemical synthesis of the compound is reported. The compound exhibits antifungal activity, as well as antioxidant activity, as indicated by its ability to scavenge reactive oxygen radicals in a chemiluminescence assay.

Chemical properties of the anion transport inhibitory binding site of arginine-specific reagents in human red blood cell membranes.

A series of arginine-specific reagents with different size and polarity have been synthesized and their inhibitory potency on sulfate exchange in resealed ghosts has been investigated. The synthesized phenylglyoxal derivatives p-nitro-, p-methyl-, p-hydroxy-, p-carboxy-, p-sulfo-, and p-azido-phenylglyoxal are found to be potent inhibitors of anion transport. The reaction between the cells and azidophenylglyoxal was performed in the dark. Exposure of the modified cells to the light was not followed by an increase in the inhibition. No cross-linking products were visible after gel electrophoresis. The rate of inactivation of sulfate flux with these reagents obeyed pseudo-first-order kinetics and increases with increasing reagents concentration and pH. Prolonged incubation of the cells with these reagents results in almost complete inhibition of the transport system. The positively charged phenylglyoxal derivative 4-(trimethylammonioacetylamido)phenylglyoxal was not able to inhibit the transport system. The hydrophobic character and the electronic properties of these reagents do not correlate with their inhibitory potency. Their electrostatic and steric effects seem to play the major role in their action.

p-Azidophenylglyoxal-epidermal growth factor: a photoactivatable affinity crosslinking reagent.

A photoaffinity derivative of highly purified 125I-labelled epidermal growth factor (125-I-EGF) has been synthesized. The heterobifunctional crosslinking reagent p-azidophenylglyoxal (PAPG) was bound to arginine residues in 125I-EGF. PAPG-125 I-EGF bound to EGF receptors on rat fibroblasts and human A431 epidermoid carcinoma cells in culture. An apparent decreased affinity of PAPG-125I-EGF for the EGF receptor is in accord with at least one arginine being at or near the EGF receptor binding site. The PAPG-125I-EGF:EGF receptor complexes on rat cells were internalized to the same extent as control EGF:receptor complexes. A431 cells treated with PAPG-125I-EGF were irradiated with ultraviolet light and the labelled proteins were analyzed by SDS-polyacrylamide gel electrophoresis. The 3 major labelled proteins had apparent molecular weights ranging from 75,000 to 200,000. Only the labelling of the 200,000-Mr protein was prevented by the addition of excess unlabelled EGF with the PAPG-125I-EGF. This molecular weight is in agreement with the reported size of the EGF receptor plus EGF. A protein with apparent molecular weight of 100,000 was labelled by 125I-EGF by an unknown mechanism which was dependent on the dose of UV light and blocked by the addition of excess unlabelled EGF.