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.     

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.     

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.     

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.     

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.     

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.     

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.     

Effects of altered α‐ and β‐branch carotenoid biosynthesis on photoprotection and whole‐plant acclimation of Arabidopsis to photo‐oxidative stress

Functions of α‐ and β‐branch carotenoids in whole‐plant acclimation to photo‐oxidative stress were studied in Arabidopsis thaliana wild‐type (wt) and carotenoid mutants, lut ein deficient (lut2, lut5), n on‐p hotochemical q uenching1 (npq1) and s uppressor of z eaxanthin‐l ess1 (szl1) npq1 double mutant. Photo‐oxidative stress was applied by exposing plants to sunflecks. The sunflecks caused reduction of chlorophyll content in all plants, but more severely in those having high α‐ to β‐branch carotenoid composition (α/β‐ratio) (lut5, szl1npq1). While this did not alter carotenoid composition in wt or lut2, which accumulates only β‐branch carotenoids, increased xanthophyll levels were found in the mutants with high α/β‐ratios (lut5, szl1npq1) or without xanthophyll‐cycle operation (npq1, szl1npq1). The PsbS protein content increased in all sunfleck plants but lut2. These changes were accompanied by no change (npq1, szl1npq1) or enhanced capacity (wt, lut5) of NPQ. Leaf mass per area increased in lut2, but decreased in wt and lut5 that showed increased NPQ. The sunflecks decelerated primary root growth in wt and npq1 having normal α/β‐ratios, but suppressed lateral root formation in lut5 and szl1npq1 having high α/β‐ratios. The results highlight the importance of proper regulation of the α‐ and β‐branch carotenoid pathways for whole‐plant acclimation, not only leaf photoprotection, under photo‐oxidative stress.     

Synthesis,photoluminescence properties and theoretical insights on 1,3‐diphenyl‐5‐(9‐anthryl)‐2‐pyrazoline and ‐1H‐pyrazole

1,3‐Diphenyl‐5‐(9‐anthryl)‐2‐pyrazoline and 1,3‐diphenyl‐5‐(9‐anthryl)‐1H‐pyrazole with an anthryl chromophore were synthesized and characterized using ¹H NMR, ¹³C NMR, FT‐IR, mass spectrometry and elemental analysis. Their optical properties were characterized by UV–vis absorption and fluorescence spectroscopy. It was observed that the absorption and fluorescence spectra of the two compounds showed a red shift with respect to that of anthracene. Pyrazole exhibited high fluorescent quantum yields (Φ_f = 0.90 in toluene) while pyrazoline showed nearly no fluorescence in solution. The significant fluorescence divergence of the two similar compounds was investigated theoretically through density functional theory (DFT) calculations. The energetically lowest‐lying state S₁ in the pyrazoline exhibited both characteristics of locally excited and electron‐transfer states that resulted in the fluorescence quenching of anthryl chromophore whereas the S₁ state in the pyrazole corresponded to an optically allowed state that led to high fluorescence quantum yields in solutions. Copyright © 2012 John Wiley & Sons, Ltd.     

Efficient Synthesis and Antioxidant Evaluation of 2‐Aryl‐3‐(Pyrimidin‐2‐yl)‐Thiazolidinones

In the present study, we reported the efficient synthesis of 11 3‐(pyrimidin‐2‐yl)‐thiazolidinones in good yields using molecular sieve as the desiccant agent. In addition, we have evaluated the antioxidant capacity of the synthesized compounds by the 2,2‐diphenyl‐2‐picrylhydrazyl hydrate (DPPH?) and the 2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid) diammonium salt (ABTS^+?) radicals scavenging assay. Six compounds showed antioxidant activity towards DPPH? (EC₅₀ between 16.13 and 49.94 µg/mL) and also demonstrated excellent activity regarding ABTS^+? (TEAC: 10.32–53.52). These results showed that compounds 3‐(pyrimidin‐2‐yl)‐thiazolidinones may be easily synthesized by a less expensive procedure and could be a good starting point to the development of new antioxidant compounds. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:445‐450, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21506     

Determination of the enantiomeric purity of the selective dopamine transporter inhibitor (+)‐R,R‐4‐(2‐benzhydryloxyethyl)‐1‐(4‐fluorobenzyl)piperidin‐3‐ol

(+)‐R ,R ‐D‐84 ((+)‐R ,R ‐4‐(2‐benzhydryloxyethyl)‐1‐(4‐fluorobenzyl)piperidin‐3‐ol) is a promising pharmacological tool for the dopamine transporter (DAT), due to its high affinity and selectivity for this target. In this study, an analytical method to ascertain the enantiomeric purity of this compound was established. For this purpose, a high‐performance liquid chromatographic (HPLC) method, based on a cellulose derived chiral stationary phase (CSP) was developed. The method was characterized concerning its specificity, linearity, and range. It was shown that the method is suitable to determine an enantiomeric excess of up to 99.8%. With only a few adjustments, this analytical CSP‐HPLC method is also well suited to separate (+)‐R ,R ‐D‐84 from its enantiomer in a semipreparative scale.