Synthesis and optical resolution of 1‐[(3‐carboxy‐1,1′‐biphenyl)‐2‐yl]‐1H‐pyrrole‐2‐carboxylic acid

Site selective mono‐ and dimetalation methods have been developed for the functionalization of 1‐[(1,1′‐biphenyl)‐2‐yl]‐1H‐pyrrole. Optical resolution of the prepared 1‐[(3‐carboxy‐1,1′‐biphenyl)‐2‐yl]pyrrole‐2‐carboxylic acid provided new atropisomeric 1‐arylpyrrole derivatives. The absolute configuration of the pure dicarboxylic acid enantiomers was determined by single crystal X‐ray diffraction and CD spectroscopy. Chirality 2009. © 2009 Wiley‐Liss, Inc.     

Synthesis of 8‐Substituted 2′‐Deoxyisoguanosines via Unprotected 8‐Brominated 2‐Amino‐2′‐deoxyadenosine

A variety of applications of 8‐alkynylated nucleosides has prompted the synthesis of new purine analogues. Bromination of unprotected 2‐amino‐2′‐deoxyadenosine with Br₂/AcOH/AcONa gives 2‐amino‐8‐bromo‐2′‐deoxyadenosine (87%). The brominated derivative is converted to 8‐alkynylated 2‐amino‐2′‐deoxyadenosines by palladium‐catalyzed Sonogashira cross‐coupling reaction via microwave assistance (81 – 95%). The resulting compounds are further transformed to 8‐alkynylated 2′‐deoxyisoguanosines (52 – 70%). The physical properties of new compounds are investigated.     

Asymmetric catalysis of homo‐coupling of 3‐substituted naphthylamine and hetero‐coupling with 3‐substituted naphthol leading to 3,3′‐dimethyl‐2,2′‐diaminobinaphthyl and ‐2‐amino‐2′‐hydroxybinaphthyl

Optically active 3,3′‐dimethyl‐2,2′‐diamino‐1,1′‐binaphthyl (DM‐DABN) and 3,3′‐dimethyl‐2‐amino‐2′‐hydroxybinaphthyl (DM‐NOBIN) derivatives were synthesized by Cu‐(?)‐sparteine complex‐catalyzed enantioselective homo‐ and hetero‐coupling of 2‐naphthylamine, respectively. The difference in enantioselectivity was observed by changing the concentration of oxygen. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

5α‐Androst‐16‐en‐3α‐ol β‐D‐Glucuronide,Precursor of 5α‐Androst‐16‐en‐3α‐ol in Human Sweat

5α‐Androst‐16‐en‐3α‐ol (α‐androstenol) is an important contributor to human axilla sweat odor. It is assumed that α‐andostenol is excreted from the apocrine glands via a H₂O‐soluble conjugate, and this precursor was formally characterized in this study for the first time in human sweat. The possible H₂O‐soluble precursors, sulfate and glucuronide derivatives, were synthesized as analytical standards, i.e., α‐androstenol, β‐androstenol sulfates, 5α‐androsta‐5,16‐dien‐3β‐ol (β‐androstadienol) sulfate, α‐androstenol β‐glucuronide, α‐androstenol α‐glucuronide, β‐androstadienol β‐glucuronide, and α‐androstenol β‐glucuronide furanose. The occurrence of α‐androstenol β‐glucuronide was established by ultra performance liquid chromatography (UPLC)/MS (heated electrospray ionization (HESI)) in negative‐ion mode in pooled human sweat, containing eccrine and apocrine secretions and collected from 25 female and 24 male underarms. Its concentration was of 79 ng/ml in female secretions and 241 ng/ml in male secretions. The release of α‐androstenol was observed after incubation of the sterile human sweat or α‐androstenol β‐glucuronide with a commercial glucuronidase enzyme, the urine‐isolated bacteria Streptococcus agalactiae, and the skin bacteria Staphylococcus warneri DSM 20316, Staphylococcus haemolyticus DSM 20263, and Propionibacterium acnes ATCC 6919, reported to have β‐glucuronidase activities. We demonstrated that if α‐ and β‐androstenols and androstadienol sulfates were present in human sweat, their concentrations would be too low to be considered as potential precursors of malodors; therefore, the H₂O‐soluble precursor of α‐androstenol in apocrine secretion should be a β‐glucuronide.     

Plasma and liver proteomic analysis of 3Z‐3‐[(1H‐pyrrol‐2‐yl)‐methylidene]‐1‐(1‐piperidinylmethyl)‐1,3‐2H‐indol‐2‐one‐induced hepatotoxicity in Wistar rats

3Z‐3‐[(1H‐pyrrol‐2‐yl)‐methylidene]‐1‐(1‐piperidinylmethyl)‐1,3‐2H‐indol‐2‐one (Z24), a synthetic anti‐angiogenic compound, inhibits the growth and metastasis of certain tumors. Previous works have shown that Z24 induces hepatotoxicity in rodents. We examined the hepatotoxic mechanism of Z24 at the protein level and looked for potential biomarkers. We used 2‐DE and MALDI‐TOF/TOF MS to analyze alternatively expressed proteins in rat liver and plasma after Z24 administration. We also examined apoptosis in rat liver and measured levels of intramitochondrial ROS and NAD(P)H redox in liver cells. We found that 22 nonredundant proteins in the liver and 11 in the plasma were differentially expressed. These proteins were involved in several important metabolic pathways, including carbohydrate, lipid, amino acid, and energy metabolism, biotransformation, apoptosis, etc. Apoptosis in rat liver was confirmed with the terminal deoxynucleotidyl transferase dUTP‐nick end labeling assay. In mitochondria, Z24 increased the ROS and decreased the NAD(P)H levels. Thus, inhibition of carbohydrate aerobic oxidation, fatty acid β‐oxidation, and oxidative phosphorylation is a potential mechanism of Z24‐induced hepatotoxicity, resulting in mitochondrial dysfunction and apoptosis‐mediated cell death. In addition, fetub protein and argininosuccinate synthase in plasma may be potential biomarkers of Z24‐induced hepatotoxicity.     

Application of NMR spectroscopy for assignment of the absolute configuration of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one

In order to assign the absolute configurations of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one ( 2a , 2b ), their esters ( 5a , 5b , 5c , 5d ) with (R)‐ or (S)‐2‐methoxyphenylacetic acid ( 4a , 4b ) have been synthesized. The absolute configurations of these compounds have been determined on the basis of NOESY correlations between the protons of the tert‐butyl group and the cyclopentane fragment of the molecules. The crucial part of this analysis was assignment of the absolute configuration at C‐5. Additionally, by calculation of the chemical shift anisotropy, δ^RS, for the relevant protons, it was also possible to confirm the absolute configurations at the C‐2 centres of compounds 2a , 2b and 5a , 5b , 5c , 5d . Chirality, 25:422–426, 2013.© 2013 Wiley Periodicals, Inc.     

Pannexin3 inhibits TNF‐α‐induced inflammatory response by suppressing NF‐κB signalling pathway in human dental pulp cells

Human dental pulp cells (HDPCs) play a crucial role in dental pulp inflammation. Pannexin 3 (Panx3), a member of Panxs (Pannexins), has been recently found to be involved in inflammation. However, the mechanism of Panx3 in human dental pulp inflammation remains unclear. In this study, the role of Panx3 in inflammatory response was firstly explored, and its potential mechanism was proposed. Immunohistochemical staining showed that Panx3 levels were diminished in inflamed human and rat dental pulp tissues. In vitro, Panx3 expression was significantly down‐regulated in HDPCs following a TNF‐α challenge in a concentration‐dependent way, which reached the lowest level at 10 ng/ml of TNF‐α. Such decrease could be reversed by MG132, a proteasome inhibitor. Unlike MG132, BAY 11‐7082, a NF‐κB inhibitor, even reinforced the inhibitory effect of TNF‐α. Quantitative real‐time PCR (qRT‐PCR) and enzyme‐linked immunosorbent assay (ELISA) were used to investigate the role of Panx3 in inflammatory response of HDPCs. TNF‐α‐induced pro‐inflammatory cytokines, interleukin (IL)‐1β and IL‐6, were significantly lessened when Panx3 was overexpressed in HDPCs. Conversely, Panx3 knockdown exacerbated the expression of pro‐inflammatory cytokines. Moreover, Western blot, dual‐luciferase reporter assay, immunofluorescence staining, qRT‐PCR and ELISA results showed that Panx3 participated in dental pulp inflammation in a NF‐κB‐dependent manner. These findings suggested that Panx3 has a defensive role in dental pulp inflammation, serving as a potential target to be exploited for the intervention of human dental pulp inflammation.     

Antiproliferative Evaluation of Some 2‐[2‐(2‐Phenylethenyl)‐cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles: DFT and Molecular Docking Study

The 2‐[2‐(2‐phenylethenyl)cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles were synthesized from the reactions of 7‐benzylidenebicyclo[3.2.0]hept‐2‐en‐6‐ones with 2‐aminobenzenethiol. The antiproliferative activities of 2‐[2‐(2‐phenylethenyl)cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles were determined against C6 (rat brain tumor) and HeLa (human cervical carcinoma cells) cell lines using BrdU cell proliferation ELISA assay. Cisplatin and 5‐fluorouracil (5‐FU) were used as standards. The most active compound was 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against C6 cell lines with IC₅₀=5.89 μm value (cisplatin, IC₅₀=14.46 μm and 5‐FU, IC₅₀=76.74 μm ). Furthermore, the most active compound was 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against HeLa cell lines with IC₅₀=3.98 μm (cisplatin, IC₅₀=37.95 μm and 5‐FU, IC₅₀=46.32 μm ). Additionally, computational studies of related molecules were performed by using B3LYP/6‐31G+(d,p) level in the gas phase. Experimental IR and NMR data were compared with the calculated results and were found to be compatible with each other. Molecular electrostatic potential (MEP) maps of the most active 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against HeLa and the most active 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against C6 were investigated, aiming to determine the region that the molecule is biologically active. Biological activities of mentioned molecules were investigated with molecular docking analyses. The appropriate target protein (PDB codes: 1 M17 for the HeLa cells and 1JQH for the C6 cells) was used for 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole and 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole molecules exhibiting the highest biological activity against HeLa and C6 cells in the docking studies. As a result, it was determined that these molecules are the best candidates for the anticancer drug.     

Use of ICD‐10 diagnoses in Danish psychiatric hospital‐based services in 2001–2007

The Danish version of the ICD-10 chapter on mental and behavioural disorders has 380 different diagnoses when three digits are used. This study examines how many of the available diagnoses were used and to what extent in Danish psychiatric hospital-based services in the period from 2001 to 2007, through an analysis of the total number of diagnoses reported to the Danish Psychiatric Central Research Register (n=1,260,097). The 50th percentile (50.1%) was reached by using 16 diagnoses (4.2% of 380 available). The three most frequently registered diagnoses were paranoid schizophrenia, alcohol dependence and adjustment disorder, used 10.2%, 8.3% and 5.9% of the times, respectively. Seven diagnoses (1.8%) were used between 1 and 4 times during the 7-year period. One hundred nine (28.7% of available diagnoses) were used less than 100 times each. These data suggest that it may be sensible to reconsider the number of diagnoses needed in the revision of the ICD-10 chapter on mental and behavioural disorders.     

Magnesium methoxide‐induced chemiluminescent decomposition of bicyclic dioxetanes bearing a 2′‐alkoxy‐2‐hydroxy‐1,1′‐binaphthyl‐7‐yl moiety

Bicyclic dioxetanes 2a–c bearing a 2′‐alkoxy‐2‐hydroxy‐1,1′‐binaphthyl‐7‐yl moiety were effectively synthesized and their base‐induced chemiluminescent decomposition was investigated by the use of alkaline metal (Na⁺ and K⁺) or Mg²⁺ alkoxide in MeOH. When 2a–c were treated with tetrabutylammonium fluoride (TBAF) in dimethyl sulfoxide (DMSO) as a reference system, they showed chemiluminescence as a flash of orange light (maximum wavelength λ_max^CL = 573–577 nm) with efficiency Φ^CL = 6–8 × 10^–2. On the other hand, for an alkaline metal (Na⁺ or K⁺) alkoxide/MeOH system, 2a–c decomposed slowly to emit a glow of chemiluminescence, the spectra of which were shifted slightly toward red from the TBAF/DMSO system, and Φ^CL (= 1.4–2.3 × 10^–3) was considerably decreased. In addition, Mg(OMe)₂ was found to play a characteristic role as a base for the chemiluminescent decomposition of 2a–c through coordination to the intermediary oxidoaryl‐substituted dioxetanes 13. Thus, Mg²⁺ increased Φ^CL to more than twice those with Na⁺ or K⁺, while it shifted λ_max^CL considerably toward blue (λ_max^CL = 550–566 nm). Copyright © 2012 John Wiley & Sons, Ltd.     

Stereoselective Synthesis of (3R)‐3‐Alkyl‐4,1‐Benzoxazepine‐2,5‐Diones

Novel 3‐alkyl‐4,1‐benzoxazepine‐2,5‐diones were synthesized in good ee exploiting the chiral pool methodology, an economical way of asymmetric synthesis. Various anthranilic acids are coupled with different α‐haloacids to afford N‐acylated anthranilic acid intermediates which undergo cyclization to (3R)‐3‐alkyl‐4,1‐benzoxazepines‐2,5‐diones. Chirality 25:865–870, 2013. © 2013 Wiley Periodicals, Inc.     

Synthesis and Antioxidant Activity of 3‐(Pyridin‐2‐ylmethyl)‐1,3‐thiazinan(thiazolidin)‐4‐ones

The antioxidant properties of two series of thiazolidinones and thiazinanones were reported. The novel six‐membered thiazinanones were synthesized from the efficient multicomponent reaction of 2‐picolylamine (2‐aminomethylpyridine), arenaldehydes, and the 3‐mercaptopropionic acid in moderate to excellent yields. These novel compounds were fully identified and characterized by NMR and GC‐MS techniques. In vitro antioxidant activities of all compounds were evaluated by 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) and 2,2′‐azinobis‐3‐ethylbenzothiazoline‐6‐sulfonic acid (ABTS) tests. The antioxidant assays of thiobarbituric acid reactive species and total thiol content levels in the cerebral cortex and liver of rats were also performed. Thiazinanone 5a showed the best radical scavenging activity in DPPH and ABTS tests, as well as reduced lipid peroxidation and increased total thiol group in biological systems. Altogether, the results may be considered a good starting point for the discovery of a new radical scavenger.     

TiO2‐coated fluoride nanoparticles for dental multimodal optical imaging

Core‐shell nanostructures associated with photonics techniques have found innumerous applications in diagnostics and therapy. In this work, we introduce a novel core‐shell nanostructure design that serves as a multimodal optical imaging contrast agent for dental adhesion evaluation. This nanostructure consists of a rare‐earth‐doped (NaYF₄:Yb 60%, Tm 0.5%)/NaYF₄ particle as the core (hexagonal prism, ~51 nm base side length) and the highly refractive TiO₂ material as the shell (~thickness of 15 nm). We show that the TiO₂ shell provides enhanced contrast for optical coherence tomography (OCT), while the rare‐earth‐doped core upconverts excitation light from 975 nm to an emission peaked at 800 nm for photoluminescence imaging. The OCT and the photoluminescence wide‐field images of human tooth were demonstrated with this nanoparticle core‐shell contrast agent. In addition, the described core‐shell nanoparticles (CSNps) were dispersed in the primer of a commercially available dental bonding system, allowing clear identification of dental adhesive layers with OCT. We evaluated that the presence of the CSNp in the adhesive induced an enhancement of 67% scattering coefficient to significantly increase the OCT contrast. Moreover, our results highlight that the upconversion photoluminescence in the near‐infrared spectrum region is suitable for image of deep dental tissue.      

A cytotoxicity,optical spectroscopy and computational binding analysis of 4‐[3‐acetyl‐5‐(acetylamino)‐2‐methyl‐2,3‐dihydro‐1,3,4‐thiadiazole‐2‐yl]phenyl benzoate in calf thymus DNA

In this study the interaction mechanism between newly synthesized 4‐(3‐acetyl‐5‐(acetylamino)‐2‐methyl‐2, 3‐dihydro‐1,3,4‐thiadiazole‐2‐yl) phenyl benzoate (thiadiazole derivative) anticancer active drug with calf thymus DNA was investigated by using various optical spectroscopy techniques along with computational technique. The absorption spectrum shows a clear shift in the lower wavelength region, which may be due to strong hypochromic effect in the ctDNA and the drug. The results of steady state fluorescence spectroscopy show that there is static quenching occurring while increasing the thiadiazole drug concentration in the ethidium bromide‐ctDNA system. Also the binding constant (K), thermo dynamical parameters of enthalpy change (ΔH°), entropy change (ΔS°) Gibbs free energy change (ΔG°) were calculated at different temperature (293 K, 298 K) and the results are in good agreement with theoretically calculated MMGBSA binding analysis. Time resolved emission spectroscopy analysis clearly explains the thiadiazole derivative competitive intercalation in the ethidium bromide‐ctDNA system. Further, molecular docking studies was carried out to understand the hydrogen bonding and hydrophobic interaction between ctDNA and thiadiazole derivative molecule. In addition the docking and molecular dynamics charge distribution analysis was done to understand the internal stability of thiadiazole derivative drug binding sites of ctDNA. The global reactivity of thiadiazole derivative such as electronegativity, electrophilicity and chemical hardness has been calculated.     

Molecular tweezers for enantiodiscrimination in NMR: Di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl benzenedicarboxylates

A series of new chiral molecular tweezers, di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl phthalate (2), isophthalate (3) and terephthalate (4), were synthesized and their structure studied by NMR and molecular mechanics. Their effectiveness as chiral solvating agents for the determination of the enantiomeric purity of chiral compounds using NMR was demonstrated. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Fluorescence modulation of 1,7‐bis(4‐hydroxy‐3‐methoxyphenyl)‐1,6‐heptadiene‐3,5‐dione by silver nanoparticles and its possible analytical application

The effects of silver nanoparticles on the photophysical properties of 1,7‐bis(4‐hydroxy‐3‐methoxyphenyl)‐1,6‐heptadiene‐3,5‐dione, popularly known as curcumin, have been investigated using optical absorption and fluorescence techniques. Although absorption spectroscopy suggests a ground‐state complex formation, fluorescence quenching data confirms a simultaneous static and dynamic quenching, inferring ground as well as excited‐state complex formation. The recovery of fluorescence quenching of the curcumin–silver nanoparticle complex in the presence of ascorbic acid or uric acid emphasizes a strong interaction between the silver nanoparticles and ascorbic acid/uric acid, suggesting that fluorescence recovery after the quenching of curcumin–silver nanoparticle complexes has potential for ascorbic acid or uric acid assay development. Copyright © 2011 John Wiley & Sons, Ltd.     

Anticonvulsant Activity of Enantiomeric N‐trans‐Cinnamoyl Derivatives of 2‐Aminopropan‐1‐ols and 2‐Aminobutan‐1‐ols

Epilepsy, one of the most frequent neurological disorders, is still insufficiently treated in about 30% of patients. As a consequence, identification of novel anticonvulsant agents is an important issue in medicinal chemistry. In the present article we report synthesis, physicochemical, and pharmacological evaluation of N‐trans‐cinnamoyl derivatives of R and S‐2‐aminopropan‐1‐ol, as well as R and S‐2‐aminobutan‐1‐ol. The structures were confirmed by spectroscopy and for derivatives of 2‐aminopropan‐1‐ols the configuration was evaluated by means of crystallography. The investigated compounds were tested in rodent models of seizures: maximal electroshock (MES) and subcutaneous pentetrazol test (scPTZ), and also in a rodent model of epileptogenesis: pilocarpine‐induced status prevention. Additionally, derivatives of 2‐aminopropan‐1‐ols were tested in benzodiazepine‐resistant electrographic status epilepticus rat model as well as in vitro for inhibition of isoenzymes of cytochrome P450. All of the tested compounds showed promising anticonvulsant activity in MES. For R(–)‐(2E)‐N‐(1‐hydroxypropan‐2‐yl)‐3‐phenylprop‐2‐enamide pharmacological parameters were found as follows: ED₅₀ = 76.7 (68.2–81.3) mg/kg (MES, mice i.p., time = 0.5 h), ED₅₀ = 127.2 (102.1–157.9) mg/kg (scPTZ, mice i.p., time = 0.25 h), TD₅₀ = 208.3 (151.4–230.6) mg/kg (rotarod, mice i.p., time = 0.25 h). Evaluation in pilocarpine status prevention proved that all of the reported compounds reduced spontaneous seizure activity and act as antiepileptogenic agents. Both enantiomers of 2‐aminopropan‐1‐ols did not influence cytochrome P450 isoenzymes activity in vitro and are likely not to interact with CYP substrates in vivo. Chirality 28:482–488, 2016. © 2016 Wiley Periodicals, Inc.     

6‐Methyl 3‐chromonyl 2,4‐thiazolidinedione/2,4‐imidazolidinedione/2‐thioxo‐imidazolidine‐4‐one compounds: novel scavengers of reactive oxygen species

The benefits of antioxidants on human health are usually ascribed to their potential ability to remove reactive oxygen species providing protection against oxidative stress. In this paper the free radicals scavenging activities of nine 6‐methyl 3‐chromonyl derivatives (CMs) were evaluated for the first time by the chemiluminescence, electron paramagnetic resonance, spin trapping and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH^?) methods. The total antioxidant capacity was also measured using a ferric‐ferrozine reagent. Compounds having a hydrogen atom at the N3‐position of the β‐ring were effective in quenching CL resulted from the KO₂/18‐crown‐6‐ether system (a source of superoxide anion radical, ) in a dose‐dependent manner over the range of 0.05–1 mmol/L [IC₅₀ ranged from 0.353 (0.04) to 0.668 (0.05) mmol/L]. The examined compounds exhibited a significant scavenging effect towards hydroxyl radicals (HO^? HO^?), produced by the Fenton reaction, and this ranged from 24.0% to 61.0%, at the concentration of 2.5 mmol/L. Furthermore, the compounds examined were also found to inhibit DPPH^? and this ranged from 51.9% to 97.4% at the same concentration. In addition, the use of the total antioxidant capacity assay confirmed that CM compounds are able to act as reductants. According to the present study, CM compounds showed effective in vitro free radical scavenging activity and may be considered as potential therapeutics to control diseases of oxidative stress‐related etiology. Copyright © 2013 John Wiley & Sons, Ltd.