- Natural-product-inspired design and synthesis of two series of compounds active against Trypanosoma cruzi: Insights into structure–activity relationship, toxicity, and mechanism of action
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Chemical scaffolds of natural products have historically been sources of inspiration for the development of novel molecules of biological relevance, including hit and lead compounds. To identify new compounds active against Trypanosoma cruzi, we designed and synthesized 46 synthetic derivatives based on the structure of two classes of natural products: tetrahydrofuran lignans (Series 1) and oxazole alkaloids (Series 2). Compounds were screened in vitro using a cellular model of T. cruzi infection. In the first series of compounds, 11 derivatives of hit compound 5 (EC50 = 1.1 μM) were found to be active; the most potent (7, 8, and 13) had EC50 values of 5.1–34.2 μM. In the second series, 17 analogs were found active at 50 μM; the most potent compounds (47, 49, 59, and 63) showed EC50 values of 24.2–49.1 μM. Active compounds were assessed for selectivity, hemocompatibility, synergistic potential, effects on mitochondrial membrane potential, and inhibitory effect on trypanothione reductase. All active compounds showed low toxicity against uninfected THP-1 cells and human erythrocytes. The potency of compounds 5 and 8 increased steadily in combination with benznidazole, indicating a synergistic effect. Furthermore, compounds 8, 47, 49, 59, and 63 inhibited parasitic mitochondria in a dose-dependent manner. Although increased reactive oxygen species levels might lead to mitochondrial effects, the results indicate that the mechanism of action of the compounds is not dependent on trypanothione reductase inhibition. In silico calculation of chemical descriptors and principal component analysis showed that the active compounds share common chemical features with other trypanocidal molecules and are predicted to have a good ADMET profile. Overall, the results suggest that the compounds are important candidates to be further studied for their potential against T. cruzi.
- Grand, Lucie,Popowycz, Florence,Schenkel, Eloir Paulo,Steindel, Mario,da Rosa, Rafael,Campos Bernardes, Lílian Sibelle,Dambrós, Bibiana Paula,H?ehr de Moraes, Milene,Jacolot, Ma?wenn
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- Design, synthesis and study of antibacterial and antitubercular activity of quinoline hydrazone hybrids
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Emerging bacterial resistance is causing widespread problems for the treatment of various infections. Therefore, the search for antimicrobials is a never-ending task. Hydrazones and quinolines possess a wide variety of biological activities. Herewith, eleven quinoline hydrazone derivatives have been designed, synthesized, characterized and evaluated for their antibacterial activity and antitubercular potential against Mtb WT H37Rv. Compounds QH-02, QH-04 and QH-05 were found to be promising compounds with an MIC value of 4 μg/mL against Mtb WT H37Rv. Compounds QH-02, QH-04, QH-05, and QH-11 were also found to be active against bacterial strains including Acinetobacter baumanii, Escherichia coli and Staphylococcus aureus. Further, we have carried out experiments to confirm the cytotoxicity of the active compounds and found them to be non-toxic.
- Eswaran, Sumesh,Shruthi, T. G.,Subramanian, Sangeetha
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p. 137 - 147
(2020/11/12)
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- COMPOUND HAVING ALKENYL GROUP AT BOTH TERMINALS, LIQUID CRYSTAL COMPOSITION AND LIQUID CRYSTAL DISPLAY ELEMENT
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PROBLEM TO BE SOLVED: To provide a liquid crystalline compound satisfying at least one of demands for physical properties such as high stability to heat or light, a high clearing point (or a high maximum temperature), low minimum temperature of a liquid crystal phase, small viscosity, suitable optical anisotropy, large dielectric anisotropy, suitable elastic modulus and good compatibility with other liquid crystalline compounds, a liquid crystal composition comprising the above compound, and a liquid crystal display element containing the composition. SOLUTION: A compound represented by formula (1) is provided. In the formula, R1 and R2 each independently represent an alkenyl group having 2 to 10 carbon atoms, or the like; ring A1, ring A2 and ring A3 each independently represent 1,4-phenylene or 1-4-phenylene in which at least one hydrogen is replaced by fluorine or chlorine; Z1 and Z2 each independently represent an alkylene having 1 to 4 carbon atoms, or the like and at least one of Z1 and Z2 may be a single bond; and a represents 1 or 2. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPO&INPIT
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Paragraph 0154
(2017/05/16)
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- Controlled Reduction of Tertiary Amides to the Corresponding Alcohols, Aldehydes, or Amines Using Dialkylboranes and Aminoborohydride Reagents
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Dialkylboranes and aminoborohydrides are mild, selective reducing agents complementary to the commonly utilized amide reducing agents, such as lithium aluminum hydride (LiAlH4) and diisobutylaluminum hydride (DIBAL) reagents. Tertiary amides were reduced using 1 or 2 equiv of various dialkylboranes. The reduction of tertiary amides required 2 equiv of 9-borabicyclo[3.3.1]nonane (9-BBN) for complete reduction to give the corresponding tertiary amines. One equivalent of sterically hindered disiamylborane reacts with tertiary amides to afford the corresponding aldehydes. Aminoborohydrides are powerful and selective reducing agents for the reduction of tertiary amides. Lithium dimethylaminoborohydride and lithium diisopropylaminoborohydride are prepared from n-butyllithium and the corresponding amine-borane. Chloromagnesium dimethylaminoborohydride (ClMg+[H3B-NMe2]-, MgAB) is prepared by the reaction of dimethylamine-borane with methylmagnesium chloride. Solutions of aminoborohydride reduce aliphatic, aromatic, and heteroaromatic tertiary amides to give the corresponding alcohol, amine, or aldehyde depending on the steric requirement of the tertiary amide and the aminoborohydride used.
- Bailey, Christopher L.,Joh, Alexander Y.,Hurley, Zefan Q.,Anderson, Christopher L.,Singaram, Bakthan
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p. 3619 - 3628
(2016/05/24)
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- Formamides as Lewis Base Catalysts in SNReactions—Efficient Transformation of Alcohols into Chlorides, Amines, and Ethers
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A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.
- Huy, Peter H.,Motsch, Sebastian,Kappler, Sarah M.
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p. 10145 - 10149
(2016/08/16)
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- Gold nanoparticles supported on magnesium oxide nanorods for oxidation of alcohols
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Gold nanoparticles supported on magnesium oxide nanorods (Au-MgO) have been synthesised by a solution based chemical reduction method. Au-MgO nanorods were found to be an efficient heterogeneous catalyst for oxidation of alcohols with hydrogen peroxide in aqueous medium at room temperature. To find out the best reaction conditions for oxidation, optimization of catalyst quantity, solvent, mole equivalence of hydrogen peroxide were carried out. The scope of the reaction was extended to several aromatic and aliphatic alcohols, product yields were quantified by gas chromatography (GC) and GC/mass spectroscopy. Heterogeneity and reusability tests were performed. The use of water as a solvent and hydrogen peroxide as co-catalyst at room temperature makes the reaction interesting from sustainable development point of view.
- Emayavaramban,Ganesh Babu,Karvembu,Kadirvelu,Dharmaraj
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p. 2517 - 2526
(2016/03/19)
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- METHOD OF CONVERTING ALCOHOL TO HALIDE
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The present invention relates to a method of converting an alcohol into a corresponding halide. This method comprises reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom. The present invention also relates to a method of converting an alcohol into a corresponding substitution product. The second method comprises: (a) performing the method of the invention of converting an alcohol into the corresponding halide; and (b) reacting the corresponding halide with a nucleophile to convert the halide into the nucleophilic substitution product.
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Page/Page column 51; 166; 170
(2017/01/02)
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- Tsuji-Wacker Oxidation of Terminal Olefins using a Palladium-Carbon Nanotube Nanohybrid
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Palladium nanoparticles supported on carbon nanotubes were used in the Tsuji-Wacker oxidation. The palladium-based nanohybrid was found to be very active in combination with cuprous chloride for the selective oxidation of terminal olefins into methyl ketones. The co-catalytic system operates under very mild and sustainable conditions (room temperature, atmospheric pressure, low catalyst loading), as opposed to previously reported catalysts, and can be recycled without any loss in activity. Give it a whack: Palladium nanoparticles supported on carbon nanotubes are used in combination with cuprous chloride for the selective Tsuji-Wacker oxidation of terminal olefins into methyl ketones. The co-catalytic system operates under very mild and sustainable conditions and can be recycled without any loss in activity.
- Donck, Simon,Gravel, Edmond,Shah, Nimesh,Jawale, Dhanaji V.,Doris, Eric,Namboothiri, Irishi N. N.
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p. 2318 - 2322
(2015/08/11)
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- Electronic structure and catalytic aspects of [(trpy)(Cl)Ru(L)]n incorporating potential non-innocent ligands, L-: 9-Oxidophenalenone and trpy: 2,2′:6′,2″-terpyridine
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The title complex [(trpy)(Cl)RuII(L)] (1) incorporating potential redox non-innocent ligands, L- = 9-oxidophenalenone and trpy = 2,2′:6′,2″-terpyridine has been structurally characterized. The crystal structure of 1 establishes the distorted octahedral arrangement, meridional coordinating mode of trpy and delocalized C-O bond distances of coordinated L-. Compound 1 displays two one-electron oxidations at E2980, 0.12 V (Ox1) and 1.32 V (Ox2) and one reduction, -1.58 V versus SCE. Predominantly ruthenium based first oxidation (Ox1) and L based second oxidation (Ox2) lead to the valence configurations of [(trpy)(Cl)Ru III(L-)]+ (1+) and [(trpy)(Cl)RuIII(L)]2+ (12+), respectively. The antiferromagnetic coupling of spins on Ru(III) (low-spin, t2g 5) and L develops a singlet (S = 0) ground state in 12+. The reduction, however, occurs at the trpy site. The electronic transitions in 1 and 1+ could be assigned based on the TD-DFT calculations. Interestingly, 1 has been established to be an efficient pre-catalyst for the oxidative cleavage of alkenes to carbonyl derivatives.
- Das, Amit,Ghosh, Tamal Kanti,Dutta Chowdhury, Abhishek,Mobin, Shaikh M.,Lahiri, Goutam Kumar
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p. 1130 - 1137
(2013/06/04)
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- Aqueous oxidation of alcohols catalysed by recoverable iron oxide nanoparticles supported on aluminosilicates
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Supported iron oxide nanoparticles on aluminosilicate catalysts were found to be efficient and easily recoverable materials in the aqueous selective oxidation of alcohols to their corresponding carbonyl compounds using hydrogen peroxide under both conventional and microwave heating. The protocol features an easy work-up, simplicity and the utilisation of mild reaction conditions as well as high selectivity toward aldehydes is highly advantageous compared to alternatively reported methodologies. The supported iron oxide nanoparticles could be easily recovered from the reaction mixture and reused several times without any loss in activity. ICP-MS results proved that there is no metal leaching observed, demonstrating the stability of the catalyst under the investigated conditions.
- Rajabi, Fatemeh,Pineda, Antonio,Naserian, Sareh,Balu, Alina Mariana,Luque, Rafael,Romero, Antonio A.
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p. 1232 - 1237
(2013/06/05)
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- Unprecedented selective oxidation of styrene derivatives using a supported iron oxide nanocatalyst in aqueous medium
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Iron oxide nanoparticles supported on mesoporous silica-type materials have been successfully utilized in the aqueous selective oxidation of alkenes under mild conditions using hydrogen peroxide as green oxidant. The supported catalyst could be easily recovered after completion of the reaction and reused several times without any loss in activity (no metal leaching observed during the reaction), constituting a facile and straightforward example of aqueous oxidation chemistry promoted by iron-based heterogeneous systems. Copyright
- Rajabi, Fatemeh,Karimi, Nafiseh,Saidi, Mohammad Reza,Primo, Ana,Varma, Rajender S.,Luque, Rafael
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experimental part
p. 1707 - 1711
(2012/07/28)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula I wherein the variables are as defined herein.
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Page/Page column 86
(2011/12/02)
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- Synthesis of bioorthogonal and crosslinking amino acids for use in peptide synthesis
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The ability to incorporate non-canonical amino acids into proteins by genetic or chemical methods allows one to introduce novel chemical properties into a protein at a defined residue. Such a residue may then be modified using common organic transformations. In this way, the structure or function of the peptide may be altered without perturbing any of the other neighbouring amino acids in the peptide chain. Here, we describe the syntheses and potential applications of multiple para-substituted phenylalanine derivatives comprising an isothiocyanate, α-diazoketone, or nitrone functionality. In all, three novel amino acids were synthesized in good overall yields. These non-canonical amino acids permit the further development of in vitro and in vivo chemoselective and regioselective bioconjugate reactions not possible with other reagents.
- Sundaram,Morgan, Ian R.,Tippmann, Eric M.
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scheme or table
p. 1381 - 1384
(2011/09/15)
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- Design, synthesis, and discovery of stilbene derivatives based on lithospermic acid B as potent protein tyrosine phosphatase 1B inhibitors
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Dihydroxy stilbene derivatives were designed based on lithospermic acid B and were prepared from 4-(chloromethyl)benzoic acid. The inhibitory activities of the novel compounds against protein tyrosine phosphatase 1B (PTP1B) were evaluated. 3,4-Dihydroxy stilbene carbonyl compounds (7, 11b, 27b) inhibited PTP1B with IC50 values comparable to molybdate, while the conjugation-extended compound (15b) showed inhibition 3-fold better than preclinical RK682. The introduction of electron withdrawing groups or amides into the second phenyl ring, or extension of the conjugation into the stilbene molecule may increase stability of the generated radicals.
- Jung, Mankil,Lee, Yongnam,Park, Moonsoo,Kim, Hanjo,Kim, Heekyeong,Lim, Eunyoung,Tak, Jungae,Sim, Minjoo,Lee, Dongeun,Park, Namsoo,Oh, Won Keun,Hur, Kyu Yeon,Kang, Eun Seok,Lee, Hyun-Chul
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p. 4481 - 4486
(2008/02/13)
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- Synthesis and evaluation of isoxazole derivatives as lysophosphatidic acid (LPA) antagonists
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A series of isoxazole derivatives were synthesized and their antagonistic activities against LPA stimulation on both LPA1/CHO cells and rHSC cells were evaluated. Among them, 3-(4-{4-[1-(2-chloro-cyclopent-1-enyl)-ethoxycarbonylamino]-isoxazol-3- yl}-benzylsulfanyl)-propionic acid (34) showed the most potent activities.
- Yamamoto, Takashi,Fujita, Koichi,Asari, Sayaka,Chiba, Akira,Kataba, Yuka,Ohsumi, Koji,Ohmuta, Naoko,Iida, Yuko,Ijichi, Chiori,Iwayama, Satoshi,Fukuchi, Naoyuki,Shoji, Masataka
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p. 3736 - 3740
(2008/02/07)
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- Visible light-induced highly selective transformation of olefin to ketone by 2,4,6-triphenylpyrylium cation encapsulated within zeolite Y
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2,4,6-Triphenylpyrylium cation encapsulated within zeolite Y promotes highly selective transformation of olefins to ketones with molecular oxygen, under visible light (λ > 400 nm) irradiation at room temperature. The Royal Society of Chemistry 2006.
- Shiraishi, Yasuhiro,Saito, Naoya,Hirai, Takayuki
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p. 773 - 775
(2008/02/03)
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- Novel azole compound
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Azole compounds represented by formula I: wherein ring A is isoxazole and the like, R1 is a substituted or unsubstituted aryl group and the like, R2 is a hydrogen atom and the like, and R3 is a substituted or unsubstituted alkyl group and the like, and pharmaceutically acceptable salts thereof inhibit the physiological activity of lysophosphatidic acid (LPA), and are useful as for the prophylaxis or treatment of diseases in which inhibition of the physiological activity of LPA is useful for the prophylaxis or treatment thereof, such as diseases involving the LPA receptor.
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Page/Page column 30
(2008/06/13)
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- DENDRON AND DENDRIMER, METHOD OF PRODUCING THE SAME, AND METHOD OF PRODUCING A THIOACETAL COMPOUND
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A dendron or dendrimer, which has, as a recurring unit of each branch, a structure of formula (I): Wherein TC designates a linkage to a former generation in the direction to a focal point of the dendron or a core of the dendrimer; TT designates a linkage to a next generation in the direction to a terminal; X is a divalent group comprised of at least one heteroatom; L?1#191 and L?2#191 each are a divalent linking group; R is a hydrogen atom or a substituent; and a method of producing a dendron or a dendrimer; and a method of producing a thioacetal compound.
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Page/Page column 32
(2008/06/13)
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- Pd-catalyzed oxidative kinetic resolution of 2-azido-1-arylethanols
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(-)-Sparteine/ Pd (II) complex in combination with oxygen as a stoichiometric oxidant, catalyses the oxidative kinetic resolution of β-azido alcohols to afford the corresponding chiral 2-azido-1-arylethanols.
- Sayyed, Iliyas Ali,Kumar, N.S.C. Ramesh,Sudalai
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p. 1533 - 1535
(2007/10/03)
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- Efficient preparation of organic substrate-RNA conjugates via in vitro transcription
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A concise synthetic way has been developed for the preparation of guanosine monophosphate derivatives carrying a decaethylene glycol spacer at their 5′-oxygen to which are attached a range of organic substrates. The four different compounds, prepared via a convergent synthetic strategy, carry a tethered benzylallyl ether residue (1a), an anthracene (1b), a benzyl carbamate residue (1c), or a primary amino group (1d), respectively. All four compounds have been successfully incorporated at the 5′-end of a 25-mer long RNA transcript via T7 RNA polymerase, and no inhibition of chain elongation could be observed. Under proper conditions, 1a and 1b can be incorporated up to 90-95% and 1c up to 68%. The amino-terminated initiator 1d is incorporated less efficiently although still up to 49%. These results show that the more hydrophobic the guanosine monophosphate derivative is, the higher is its enzymatic incorporation.
- Fiammengo, Roberto,Musilek, Kamil,Jaeschke, Andres
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p. 9271 - 9276
(2007/10/03)
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- Oxidation of benzylic alcohols and ethers to carbonyl derivatives by nitric acid in dichloromethane
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Nitric acid in dichloromethane may be successfully employed for the oxidation of benzylic alcohols and ethers to the corresponding carbonyl compounds. The proposed method proved to be of general applicability, affording very good yields of aldehydes and ketones and showing interesting chemoselectivity in many instances, allowing competitive aromatic nitration to be avoided, as well as - in the case of aldehydes - any further oxidation to carboxylic acids. The reaction probably proceeds by a radical mechanism, the active species in the oxidation process being NO2. Competitive formation of nitro esters was observed in some cases, whereas poor results were obtained with allylic and non-benzylic substrates. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Strazzolini, Paolo,Runcio, Antonio
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p. 526 - 536
(2007/10/03)
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- Substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs as activators of caspases and inducers of apoptosis and the use thereof
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The present invention is directed to substituted indole-2-carboxylic acid benzylidene-hydrazides and analogs thereof, represented by the general Formula I: wherein X, Ar1, R2-R6 and R12 are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. The compounds of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
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- Stereoselective synthesis of HIV-1 protease inhibitor, DMP 323
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DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C2 symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led te intermediates which were easily purified without chromatography. Additionally, a one-pot, high yield process was developed te prepare the alkylating agent, 4-[(triphenylmethoxy)methyl]benzyl chloride from 1,4-benzenedimethanol.
- Pierce,Pierce, Michael E.,Harris,Harris, Gregory D.,Islam,Islam, Qamrul,Radesca,Radesca, Lilian A.,Storace,Storace, Louis,Waltermire,Waltermire, Robert E.,Wat,Wat, Ed,Jadhav,Jadhav, Prabhakar K.,Emmett,Emmett, George C.
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p. 444 - 450
(2007/10/02)
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- A new route to water soluble porphyrins: Phosphonium and ammonium type cationic porphyrins and self-assembly
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From a precursor porphyrin, tetrakis(p-chloromethylphenyl)porphyrin, the novel phosphoniumyl and ammoniumyl cationic porphyrins are synthesized, and the unusual spontaneous assembly for the two cationic porphyrins is discussed.
- Jin, Ren-Hua,Aoki, Shinya,Shima, Kensuke
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p. 1939 - 1940
(2007/10/03)
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- Polar Radicals. 15. Interpretation of Substituent Effects on the Mechanism of Electrolytic Reduction of the Carbon-Halogen Bond in Series of Substituted Benzyl Halides
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The electrochemical polarographic reduction of a series of substituted benzyl chlorides and benzyl bromides showed half-wave potentials which gave excellent Hammett linear free-energy correlations for each series.These correlations were obtained using ?- substituent constants.The correlation with ?- suggests that the potential-determining electrochemical process involves carbon-halogen bond breaking or, alternatively, radical anion intermediate formation.The Hammett ρ values for each correlation were calculated; their magnitudes, Cl>Br, were in the inverse order of their reactivity toward chemical reduction.As in the case of trialkyltin hydride reduction, both ρ values were positive.The results of the polarographic electroreduction of benzyl iodide and benzylmercuric iodide confirmed the previously reported mechanism for reduction;namely, that the iodide underwent reaction with mercury to form benzylmercuric iodide, which was subsequently reduced, as was benzylmercuric iodide itself, by a process having two distinct polarographic waves.The half-wave potentials for the second wave (the wave at the most negative potential) for series of substituted benzyl iodides and benzylmercuric iodides were both found to give excellent Hammett correlation, having positive ρ values.The correlations were both obtained by using ?- substituent constants.The success of the use of these substituent constants was taken as a confirmation of the suggestion, previously made, that the second step in the electroreduction was the reduction of the benzylmercuryl radical, and suggests that the process is concerted with carbon-mercury bond rupture.
- Tanner, Dennis D.,Plambeck, James A.,Reed, Darwin W.,Mojelski, Thomas W.
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p. 5177 - 5183
(2007/10/02)
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