Novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes: Synthesis,characterization, acetylcholinesterase,butyrylcholinesterase, and carbonic anhydrase inhibitory properties

The thiolation reaction was carried out in a benzene solution at 80°C and p‐substituted ketones and mercaptoacetic acid in a molar ratio (1:4) of in the presence of a catalytic amount of toluene sulfonic acids. The enzyme inhibition activities of the novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes derivatives were investigated. These novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes derivatives showed good inhibitory action against acetylcholinesterase (AChE) butyrylcholinesterase (BChE), and human carbonic anhydrase I and II isoforms (hCA I and II). AChE inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. Many clinically established drugs are carbonic anhydrase inhibitors, and it is highly anticipated that many more will eventually find their way into the market. The novel synthesized compounds inhibited AChE and BChE with K_i values in the range of 0.64–1.47 nM and 9.11–48.12 nM, respectively. On the other hand, hCA I and II were effectively inhibited by these compounds, with K_i values between 63.27–132.34 and of 29.63–127.31 nM, respectively.     

LiTFSI‐Free Spiro‐OMeTAD‐Based Perovskite Solar Cells with Power Conversion Efficiencies Exceeding 19%

To date, the most efficient perovskite solar cells (PSCs) employ an n–i–p device architecture that uses a 2,2′,7,7′‐tetrakis(N,N‐di‐p‐methoxyphenyl‐amine)‐9,9′‐spirobifluorene (spiro‐OMeTAD) hole‐transporting material (HTM), which achieves optimum conductivity with the addition of lithium bis(trifluoromethane)sulfonimide (LiTFSI) and air exposure. However, this additive along with its oxidation process leads to poor reproducibility and is detrimental to stability. Herein, a dicationic salt spiro‐OMeTAD(TFSI)₂, is employed as an effective p‐dopant to achieve power conversion efficiencies of 19.3% and 18.3% (apertures of 0.16 and 1.00 cm²) with excellent reproducibility in the absence of LiTFSI and air exposure. As far as it is known, these are the highest‐performing n–i–p PSCs without LiTFSI or air exposure. Comprehensive analysis demonstrates that precise control of the proportion of [spiro‐OMeTAD]⁺ directly provides high conductivity in HTM films with low series resistance, fast hole extraction, and lower interfacial charge recombination. Moreover, the spiro‐OMeTAD(TFSI)₂‐doped devices show improved stability, benefitting from well‐retained HTM morphology without forming aggregates or voids when tested under an ambient atmosphere. A facile approach is presented to fabricate highly efficient PSCs by replacing LiTFSI with spiro‐OMeTAD(TFSI)₂. Furthermore, this study provides an insight into the relationship between device performance and the HTM doping level.     

Synthetic Method for 2,2'‐Disubstituted Fluorinated Binaphthyl Derivatives and Application as Chiral Source in Design of Chiral Mono‐Phosphoric Acid Catalyst

A practical synthetic method for 2,2'‐disubstituted fluorinated binaphthyl derivatives was achieved using magnesium bis(2,2,6,6‐tetramethylpiperamide) [Mg(TMP)₂], prepared from LiTMP (2 equiv) and MgBr₂ (1 equiv), which allows for access to a variety of fluorinated binaphthyl compounds. The utility of the fluorinated binaphthyl backbone was evaluated in F₁₀BINOL derived chiral mono‐phosphoric acid (R)‐ 19 as the chiral Brønsted acid catalyst. The catalyst (R)‐ 19 performs exceptionally well in the catalytic enantioselective imino‐ene reaction, demonstrating the potential of a fluorinated binaphthyl framework. Chirality 27:464–475, 2015. © 2015 Wiley Periodicals, Inc.     

Resolution of 1‐n‐Butyl‐3‐Methyl‐3‐Phospholene 1‐Oxide With TADDOL Derivatives and Calcium Salts of O,O'‐Dibenzoyl‐(2R,3R)‐ or O,O'‐di‐p‐Toluoyl‐(2R,3R)‐tartaric Acid

The resolution methods applying (?)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane (“TADDOL”), (?)‐(2R,3R)‐α,α,α',α'‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol (“spiro‐TADDOL”), as well as the acidic and neutral Ca²⁺ salts of (?)‐O,O'‐dibenzoyl‐ and (?)‐O,O'‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid were extended for the preparation of 1‐n‐butyl‐3‐methyl‐3‐phospholene 1‐oxide in optically active form. In one case, the intermediate diastereomeric complex could be identified by single‐crystal X‐ray analysis. The absolute P‐configuration of the enantiomers of the phospholene oxide was also determined by comparing the experimentally obtained and calculated CD spectra. Chirality 26:174–182, 2014. © 2014 Wiley Periodicals, Inc.     

Asymmetric Borane Reduction of Prochiral Ketones Catalyzed By Helical Poly[(S)‐3‐vinyl‐2,2'‐dihydroxy‐1,1'‐binaphthyl]

The application of helical poly[(S)‐3‐vinyl‐2,2'‐dihydroxy‐1, 1'‐binaphthyl] ( L* ) in the asymmetric borane reduction of prochiral ketones was studied. The results showed that L* had excellent catalytic activity as well as enantioselectivity, giving up to 96% yield and up to 99% enantiomeric excess (ee) of the corresponding secondary alcohol at 25 °C. Moreover, L* can be easily recovered and reused without loss of catalytic activity. Chirality 27:422–424, 2015. © 2015 Wiley Periodicals, Inc.     

Novel Oxaliplatin Derivatives with 1‐(Substituted Benzyl)azetidine‐3,3‐dicarboxylate Anions. Synthesis,Cytotoxicity, and Interaction with DNA

A series of oxaliplatin derivatives with (1R,2R)‐N¹‐alkyl‐1,2‐cyclohexane‐1,2‐diamine (alkyl=Bu or ⁱPr) as carrier ligands and 1‐(methoxy‐ or methyl‐substituted benzyl)azetidine‐3,3‐dicarboxylate anions as leaving groups were synthesized and spectrally characterized. Generally, Complexes 10 – 15 with an ⁱPr substituent at N(1) showed higher activities in vitro than carboplatin against MCF‐7 human breast carcinoma and A549 human non‐small‐cell lung cell lines, although they were less potent than oxaliplatin. The typical complex 14 exhibited cytotoxicity superior to that of carboplatin and comparable to that of oxaliplatin against two selected tumor cell lines. Additionally, agarose gel electrophoresis was applied to investigate the DNA‐cleavage ability of complex 14 , which demonstrated that it has a different mode of DNA distortion from that of oxaliplatin.     

Unexpected Loss of Stereoselectivity in Ring‐Opening Reaction of 2‐Alkoxy‐2‐Thio‐1,3,2‐Oxathiaphospholanes With a Pyrophosphate Anion

A reaction of DBU promoted ring opening in nucleoside‐3'‐O‐ and nucleoside‐5'‐O‐(2‐thio‐4,4‐pentamethylene‐1,3,2‐oxathiaphospholane) monomers with a pyrophosphate or a methylenediphosphonate anion proceeds with substantial loss of stereoselectivity. Depending on the absolute configuration of the phosphorus atom, so far widely accepted the stereoretentive mechanism of condensation is accompanied by a stereoinvertive one, most likely employing an intramolecular ligand–ligand exchange in an uncharged intermediate. Chirality 27:155–122, 2015. © 2014 Wiley Periodicals, Inc     

Room temperature and highly enantioselective additions of alkyltitanium reagents to aldehydes catalyzed by a titanium catalyst of (R)‐h8‐binol

Three alkyltitanium reagents of RTi(O‐i‐Pr)₃ (R = Cy ( 1a ), i‐Bu ( 1b ), and n‐Bu ( 1c )) were prepared in good yields. The high‐resolution mass spectroscopy showed that 1b and 1 c in the gas phase are monomeric species. However, the solid state of 1a revealed a dimeric structure. Asymmetric additions of 1a , 1b , 1c to aldehydes catalyzed by a titanium catalyst of (R)‐H₈‐BINOL were studied at room temperature. The reactions produced desired secondary alcohols in good yields with good to excellent enantioselectivities of up to 94% ee. Reactivity and enantioselectivity differences, in terms of steric bulkiness of the R nucleophiles, are herein described. The addition reactions of secondary c‐hexyl to aldehydes were slower than the reactions of primary i‐butyl or n‐butyl nucleophiles. For the primary alkyls, lower enantioselectivities were obtained for products from addition reactions of the linear n‐butyl as compared with the enantioselectivities of products from the addition reactions of the branched i‐butyl group. The same stereochemistry of RTi(O‐i‐Pr)₃ addition reactions as the addition reactions of organozinc, organoaluminum, Grignard, or organolithium reagents directly supports the argument of that titanium‐catalyzed addition reactions of aldehydes involve an addition of an organotitanium nucleophile. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Noncovalent Immobilization of Ionic‐tagged Box‐Cu(OAc)2 Complex and Its Application in Asymmetric Henry Reaction

Immobilized Cu(OAc)₂‐bis(oxazolines) via hydrogen bonding by SBA‐15 was applied to asymmetric Henry reaction, and good enantioselectivities were obtained (up to 83% ee) between 2‐methoxybenzaldehyde and CH₃NO₂ in isopropyl alcohol (iPrOH). The catalyst could be reused seven times without any obvious loss in enantioselectivity. For the first time, this facile and clean immobilization method is applied to the use of bis(oxazolines) complexes. Chirality 24:1092‐1095, 2012. © 2012 Wiley Periodicals, Inc.     

Sequence‐dependent folding and unfolding of ligand‐bound purine riboswitches

Riboswitch regulation of gene expression requires ligand‐mediated RNA folding. From the fluorescence lifetime distribution of bound 2‐aminopurine ligand, we resolve three RNA conformers (C_o, C_i, C_c) of the liganded G‐ and A‐sensing riboswitches from Bacillus subtilis. The ligand binding affinities, and sensitivity to Mg²⁺, together with results from mutagenesis, suggest that C_o and C_i are partially unfolded species compromised in key loop‐loop interactions present in the fully folded C_c. These data verify that the ligand‐bound riboswitches may dynamically fold and unfold in solution, and reveal differences in the distribution of folded states between two structurally homologous purine riboswitches: Ligand‐mediated folding of the G‐sensing riboswitch is more effective, less dependent on Mg²⁺, and less debilitated by mutation, than the A‐sensing riboswitch, which remains more unfolded in its liganded state. We propose that these sequence‐dependent RNA dynamics, which adjust the balance of ligand‐mediated folding and unfolding, enable different degrees of kinetic discrimination in ligand binding, and fine‐tuning of gene regulatory mechanisms. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 953–965, 2009. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com     

Asymmetric epoxidation of cinnamyl alcohol with optically active titanium complexes

A family of titanium(IV) alkoxo compounds [{Ti(O‐i‐Pr)₂(OR)₂}₂] 1–4 prepared by alcohol exchange of Ti(O‐i‐Pr)₄ and a chiral higher‐boiling alcohol [ROH = 1,2:3,4‐di‐O‐isopropylidene‐α‐d ‐galactopyranose, 1,2:5,6‐di‐O‐isopropylidene‐α‐d ‐glucofuranose, (1R,2S,5R)‐(?)‐menthol, (1S‐endo)‐(?)‐borneol, (1S,2R,5S)‐(+)‐menthol, and (+)‐borneol] has been tested to evaluate their catalytic activity and stereoselectivity in the asymmetric epoxidation of cinnamyl alcohol. © 2005 Wiley‐Liss, Inc. Chirality     

Copper‐Chiral Camphor β‐Amino Alcohol Complex Catalyzed Asymmetric Henry Reaction

Four novel chiral amino alcohols were synthesized from D‐(+)‐camphor and utilized as ligands in a Cu(I)‐catalyzed asymmetric Henry reaction. The reactions were carried out under mild conditions with excellent enantioselectivities and moderate yields without the exclusion of air or moisture. The highest enantioselectivity was observed up to 94% enantiomeric excess (ee) with ligand L1 in toluene at room temperature. Chirality 27:761–765, 2015. © 2015 Wiley Periodicals, Inc.     

Resolution of Enantiomers of Novel C2‐Symmetric Aminobisphosphinic Acids via Diastereomeric Salt Formation With Quinine

C₂‐symmetric N,N‐bis(phosphinomethyl)amines were prepared by the thermal reaction of aromatic aldehydes with ammonia and hypophosphorus acid as previously described. Both enantiomers of C₂‐symmetric N,N‐bis(phosphinomethyl)amine were obtained in a high enantiomeric purity through the diastereomeric salt formation with (–)‐quinine, and subsequent fractional crystallization. X‐ray crystallographic analysis of one of the diastereomeric salts clearly revealed that (–)‐quinine could be an efficient resolving agent for obtaining the single enantiomer (R,R)‐N,N‐bis(phosphinomethyl)amine. Chirality 27:71–74, 2015. © 2014 Wiley Periodicals, Inc.     

Determination of the Enantiomerization Barrier of the Residual Enantiomers of C3‐Symmetric Tris[3‐(1‐Methyl‐2‐Alkyl)Indolyl]Phosphane Oxides: Case Study of a Multitasking HPLC Investigation Based on an Immobilized Polysaccharide Stationary Phase

The residual enantiomers of three tris‐(3‐indolyl)‐phosphane oxides bearing different alkyl groups (methyl, ethyl or i‐propyl) in position 2 of the indole rings constituting the blades were separated on the immobilized type Chiralpak IC column in polar organic and reversed‐phase modes. The good enantioselectivity and versatility of the IC CSP allowed easy isolation of the enantiomerically highly enriched samples suitable for configurational stability studies. The enantiomerization barriers of residual phosphane oxides were evaluated both by off‐column techniques (CD signal and enantiomeric purity decay kinetics) and by dynamic enantioselective high‐performance liquid chromatography (HPLC). Chirality 27:888–899, 2015. © 2015 Wiley Periodicals, Inc.     

Copper Salts Doped Spiro‐OMeTAD for High‐Performance Perovskite Solar Cells

The development of effective and stable hole transporting materials (HTMs) is very important for achieving high‐performance planar perovskite solar cells (PSCs). Herein, copper salts (cuprous thiocyanate (CuSCN) or cuprous iodide (CuI)) doped 2,2,7,7‐tetrakis(N,N‐di‐p‐methoxyphenylamine)‐9,9‐spirobifluorene (spiro‐OMeTAD) based on a solution processing as the HTM in PSCs is demonstrated. The incorporation of CuSCN (or CuI) realizes a p‐type doping with efficient charge transfer complex, which results in improved film conductivity and hole mobility in spiro‐OMeTAD:CuSCN (or CuI) composite films. As a result, the PCE is largely improved from 14.82% to 18.02% due to obvious enhancements in the cell parameters of short‐circuit current density and fill factor. Besides the HTM role, the composite film can suppress the film aggregation and crystallization of spiro‐OMeTAD films with reduced pinholes and voids, which slows down the perovskite decomposition by avoiding the moisture infiltration to some extent. The finding in this work provides a simple method to improve the efficiency and stability of planar perovskite solar cells.     

ω‐Turn: A novel β‐turn mimic in globular proteins stabilized by main‐chain to side‐chain CH···O interaction

Mimicry of structural motifs is a common feature in proteins. The 10‐membered hydrogen‐bonded ring involving the main‐chain C?O in a β‐turn can be formed using a side‐chain carbonyl group leading to Asx‐turn. We show that the N? H component of hydrogen bond can be replaced by a C^γ‐H group in the side chain, culminating in a nonconventional C? H···O interaction. Because of its shape this β‐turn mimic is designated as ω‐turn, which is found to occur ～three times per 100 residues. Three residues (i to i + 2) constitute the turn with the C? H···O interaction occurring between the terminal residues, constraining the torsion angles ?_{i + 1}, ψ_{i + 1}, ?_{i + 2} and χ′_{1(i + 2)} (using the interacting C^γ atom). Based on these angles there are two types of ω‐turns, each of which can be further divided into two groups. C^β‐branched side‐chains, and Met and Gln have high propensities to occur at i + 2; for the last two residues the carbonyl oxygen may participate in an additional interaction involving the S and amino group, respectively. With Cys occupying the i + 1 position, such turns are found in the metal‐binding sites. N‐linked glycosylation occurs at the consensus pattern Asn‐Xaa‐Ser/Thr; with Thr at i + 2, the sequence can adopt the secondary structure of a ω‐turn, which may be the recognition site for protein modification. Location between two β‐strands is the most common occurrence in protein tertiary structure, and being generally exposed ω‐turn may constitute the antigenic determinant site. It is a stable scaffold and may be used in protein engineering and peptide design. Proteins 2015; 83:203–214. © 2014 Wiley Periodicals, Inc.     

Evaluation of antimicrobial,antibiofilm and carbonic anhydrase inhibition profiles of 1,3‐bis‐chalcone derivatives

A series of 1,3‐bis‐chalcone derivatives ( 3a‐i, 6a‐i and 8 ) were synthesized and evaluated antimicrobial, antibiofilm and carbonic anhydrase inhibition activities. In this evaluation, 6f was found to be the most active compound showing the same effect as the positive control against Bacillus subtilis and Streptococcus pyogenes in terms of antimicrobial activity. Biofilm structures formed by microorganisms were damaged by compounds at the minimum inhibitory concentration value between 0.5% and 97%.1,3‐bis‐chalcones ( 3a‐i, 6a‐i and 8 ) showed good inhibitory action against human (h) carbonic anhydrase (CA) isoforms I and II. hCA I and II were effectively inhibited by these compounds, with K _i values in the range of 94.33 ± 13.26 to 787.38 ± 82.64 nM for hCA I, and of 100.37 ± 11.41 to 801.76 ± 91.11 nM for hCA II, respectively. In contrast, acetazolamide clinically used as CA inhibitor showed K _i value of 1054.38 ± 207.33 nM against hCA I, and 983.78 ± 251.08 nM against hCA II, respectively.     

A Dopant‐Free Polymeric Hole‐Transporting Material Enabled High Fill Factor Over 81% for Highly Efficient Perovskite Solar Cells

Although perovskite solar cells (PVSCs) have achieved rapid progress in the past few years, most of the high‐performance device results are based on the doped small molecule hole‐transporting material (HTM), spiro‐OMeTAD, which affects their long‐term stability. In addition, some defects from under‐coordinated Pb atoms on the surface of perovskite films can also result in nonradiative recombination to affect device performance. To alleviate these problems, a dopant‐free HTM based on a donor‐acceptor polymer, PBT1‐C, synthesized from the copolymerization between the benzodithiophene and 1,3‐bis(4‐(2‐ethylhexyl)thiophen‐2‐yl)‐5,7‐bis(2‐alkyl)benzo[1,2‐c:4,5‐c′]dithiophene‐4,8‐dione units is introduced. PBT1‐C not only possesses excellent hole mobility, but is also able to passivate the surface traps of the perovskite films. The derived PVSC shows a high power conversion efficiency of 19.06% with a very high fill factor of 81.22%, which is the highest reported for dopant‐free polymeric HTMs. The results from photoluminescence and trap density of states measurements validate that PBT1‐C can effectively passivate both surface and grain boundary traps of the perovskite.     

Anti‐Tumor‐Initiating Effects of Spiro‐biflavonoids from Abies sachalinensis

Cancer chemoprevention, the prevention of cancer by ingestion of chemical agents that reduce the risk of carcinogenesis, is one of the potent ways to reduce morbidity and mortality. We have been searching for cancer chemopreventive agents from the leaves and barks of coniferous trees that have been treated as waste in the forestry industry. We have previously reported the isolation of spiro‐biflavonoids, named as abiesinols, and a neolignan from the MeOH extract of the bark of Abies sachalinensis. These compounds were tested for their inhibitory effects on the activation of (±)‐(E)‐methyl‐2‐[(E)‐hydroxyimino]‐5‐nitro‐6‐methoxyhex‐3‐enamide (NOR 1), a nitric oxide (NO) donor, as a primary screening test for anti‐tumor initiators. All compounds tested exhibited potent inhibitory effects on NOR 1 activation. Furthermore, abiesinol A, bearing a spiro‐biflavonoid skeleton, showed remarkable anti‐tumor‐initiating activity in the in vivo two‐stage mouse skin carcinogenesis test using peroxynitrite (ONOO^?; PN) as the initiator and 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) as the promoter.     

BAPTA‐AM dramatically improves maturation and development of bovine oocytes from grade‐3 cumulus‐oocyte complexes

Intracellular free calcium ([Ca²⁺]_i) is essential for oocyte maturation and early embryonic development. Here, we investigated the role of [Ca²⁺]_i in oocytes from cumulus‐oocyte complexes (COCs) with respect to maturation and early embryonic development, using the calcium‐buffering agent BAPTA‐AM (1,2‐bis[2‐aminophenoxy]ethane‐N,N,N′,N′‐tetraacetic acid tetrakis [acetoxymethyl ester]). COCs were graded based on compactness of the cumulus mass and appearance of the cytoplasm, with Grade 1 indicating higher quality and developmental potential than Grade 3. Results showed that: (i) [Ca²⁺]_i in metaphase‐II (MII) oocytes from Grade‐3 COCs was significantly higher than those from Grade‐1 COCs, and was significantly reduced by BAPTA‐AM; (ii) nuclear maturation of oocytes from Grade‐3 COCs treated with BAPTA‐AM was enhanced compared to untreated COCs; (iii) protein abundance of Cyclin B and oocyte‐specific Histone 1 (H1FOO) was improved in MII oocytes from Grade‐3 COCs treated with BAPTA‐AM; (iv) Ca²⁺ transients were triggered in each group upon fertilization, and the amplitude of [Ca²⁺]_i oscillations increased in the Grade‐3 group upon treatment with BAPTA‐AM, with the magnitude approaching that of the Grade‐1 group; and (v) cleavage rates and blastocyst‐formation rates were improved in the Grade‐3 group treated with BAPTA‐AM compared to untreated controls following in vitro fertilization and parthenogenetic activation. Therefore, BAPTA‐AM dramatically improved oocyte maturation, oocyte quality, and embryonic development of oocytes from Grade‐3 COCs.