- Cytochrome p450 can epoxidize an oxepin to a reactive 2,3-epoxyoxepin intermediate: Potential insights into metabolic ring-opening of benzene
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Dimethyldioxirane epoxidizes 4,5-benzoxepin to form the reactive 2,3-epoxyoxepin intermediate followed by very rapid ring-opening to an o-xylylene that immediately isomerizes to the stable product 1H-2-benzopyran-1-carboxaldehyde. The present study demonstrates that separate incubations of 4,5-benzoxepin with three cytochrome P450 isoforms (2E1, 1A2, and 3A4) as well as pooled human liver microsomes (pHLM) also produce 1H-2-benzopyran-1-carboxaldehyde as the major product, likely via the 2,3-epoxyoxepin. The reaction of 4,5-benzoxepin with cerium (IV) ammonium nitrate (CAN) yields a dimeric oxidized molecule that is also a lesser product of the P450 oxidation of 4,5-benzoxepin. The observation that P450 enzymes epoxidize 4,5-benzoxepin suggests that the 2,3-epoxidation of oxepin is a major pathway for the ring-opening metabolism of benzene to muconaldehyde.
- Cote, Noah A.,Fitzgerald, Ryan W.,Greenberg, Arthur,Weaver-Guevara, Holly M.
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- Asymmetric synthesis of azolium-based 1,2,3,4-tetrahydronaphthalen-2-ols through lipase-catalyzed resolutions
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Abstract A series of racemic trans-1,2,3,4-tetrahydronaphthalen-2-ols bearing an azole nucleus at the C-1 or C-3 position has been synthesized by ring opening reactions of the corresponding epoxides using imidazole or 1,2,4-triazole. The kinetic resolutions of these racemates were undertaken through transesterification processes, finding good levels of activities and high to excellent enantiodiscrimination values for the Pseudomonas cepacia lipase immobilized on a ceramic carrier. Investigations into the optimum reaction conditions were carried out by consideration of different organic solvents, temperatures, enzyme loadings, and reaction times. With the best conditions in hand, the experiments were later carried out toward the resolution of the related racemic cis-alcohols, which were previously obtained through a Mitsunobu and deprotection chemical sequence from the trans-stereoisomers.
- Méndez-Sánchez, Daniel,Ríos-Lombardía, Nicolás,Gotor, Vicente,Gotor-Fernández, Vicente
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- Synthesis and labeling of a piperazine-based library of 11C-labeled ligands for imaging of the vesicular acetylcholine transporter
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The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a-f, six potential VAChT PET tracers, [11C]-(±)5a-f, were 11C-labeled by a palladium (0)-mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [11C]-(±) 5a-f were obtained in radiochemical purities >95% with decay-corrected radiochemical yields and specific radioactivities between 4-25% and 124-597 GBq/μmol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [ 11C]-(±)5d and [11C]-(±)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine-based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach A library of six piperazine-based ligands for the vesicular acetylcholine transporter were synthesized and labeled from a common precursor, commercially available aryl iodides and [11C]carbon monoxide. Labeled compounds were isolated with radiochemical yields ranging from 4% to 25% and with specific radioactivities between 124 and 597 GBq/μmol. As a simple preclinical evaluation of the labeled compounds, their binding potential to VAChT was assessed by autoradiography. Copyright
- Bergman, Sara,Estrada, Sergio,Rahman, Rashidur,Blomgren, Andreas,Larhed, Mats,Svedberg, Marie,Thibblin, Alf,Antoni, Gunnar
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- Crystalline Hetero-Stereocomplexed Polycarbonates Produced from Amorphous Opposite Enantiomers Having Different Chemical Structures
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Abstract Stereocomplexation is the stereoselective interaction between two opposite enantiomeric polymers through an interlocked orderly assembly. Most studies focus on the stereocomplex formation from the crystalline opposite enantiomers having the identical structure; nevertheless, rare examples were reported regarding the crystalline stereocomplexes from enantiomeric polymers having different chemical structures. Herein we show a strategy for polymer orderly assembly through the formation of crystalline hetero-stereocomplexed polymeric materials by the cocrystallization of amorphous isotactic polycarbonates with different chemical structures and opposite configurations. The behaviors in the crystalline state are significantly different from that of the component enantiomeric polymers or their homo-stereocomplexes. This study is expected to open up a new way to prepare various semicrystalline materials having a wide variety of physical properties and degradability. Mixed enantiomers: A unique strategy for polymer assembly was demonstrated through the formation of crystalline hetero-stereocomplexed polymeric materials by the cocrystallization of amorphous isotactic polycarbonates with opposite configurations and different chemical structures. This study is expected to open up a new way to prepare various semicrystalline materials with a wide variety of physical properties and degradability.
- Liu, Ye,Wang, Meng,Ren, Wei-Min,Xu, Yue-Chao,Lu, Xiao-Bing
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Read Online
- Selective Isomerization via Transient Thermodynamic Control: Dynamic Epimerization of trans to cis Diols
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Traditional approaches to stereoselective synthesis require high levels of enantio- and diastereocontrol in every step that forms a new stereocenter. Here, we report an alternative approach, in which the stereochemistry of organic substrates is selectivel
- Macmillan, David W. C.,Oswood, Christian J.
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supporting information
p. 93 - 98
(2022/01/03)
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- PEPTIDE CONJUGATES OF CYTOTOXINS AS THERAPEUTICS
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The present invention relates to peptide conjugates of cytotoxins such as topoisomerase I inhibitors which are useful for the treatment of diseases such as cancer.
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Paragraph 0413-0415
(2021/01/25)
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- Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases
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Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease - Trypanosoma cruzi. These SMAIs exerted potent, reversible inhibition of cruzain (Ki? = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.
- Li, Linfeng,Chenna, Bala C.,Yang, Kai S.,Cole, Taylor R.,Goodall, Zachary T.,Giardini, Miriam,Moghadamchargari, Zahra,Hernandez, Elizabeth A.,Gomez, Jana,Calvet, Claudia M.,Bernatchez, Jean A.,Mellott, Drake M.,Zhu, Jiyun,Rademacher, Andrew,Thomas, Diane,Blankenship, Lauren R.,Drelich, Aleksandra,Laganowsky, Arthur,Tseng, Chien-Te K.,Liu, Wenshe R.,Wand, A. Joshua,Cruz-Reyes, Jorge,Siqueira-Neto, Jair L.,Meek, Thomas D.
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p. 11267 - 11287
(2021/08/16)
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- INHINITORS OF GLI1 AS THERAPEUTIC AGENTS
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This disclosure relates to compounds, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases related to glioma- associated oncogene (Gli) expression. More particularly, this disclosure relate
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Paragraph 0177
(2020/06/10)
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- Carbon Dioxide Copolymerization Study with a Sterically Encumbering Naphthalene-Derived Oxide
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Poly(1,4-dihydronaphthalene carbonate) has been prepared via the catalytic coupling of carbon dioxide and 1,4-dihydronaphthalene oxide using chromium(III) catalysts. The copolymer formation is found to be greatly dependent on the steric environment around the metal center. Traditional (salen)CrIIIX/cocatalyst systems bearing bulky t-butyl groups hinder the approach of the large monomer, significantly diminishing polymer chain growth and providing the entropically favored cyclic byproduct in excess. In contrast, employing the sterically unencumbered azaannulene-derived catalyst, (tmtaa)CrIIIX/cocatalyst system (tmtaa = tetramethyltetraazaannulene) shows polymer selectivity close to 90% with three times the activity (TOF = 20-30 h-1). With the use of a bifunctional (salen)CrIII catalyst, even higher polymer selectivity (>90%) can be observed. The complete synthesis of a new bifunctional tetraazaannulene ligand for a more effective catalyst is also described herein.
- Darensbourg, Donald J.,Kyran, Samuel J.
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p. 5421 - 5430
(2015/09/15)
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- Chemoenzymatic epoxidation of alkenes based on peracid formation by a Rhizomucor miehei lipase-catalyzed perhydrolysis reaction
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A chemoenzymatic and selective method for the epoxidation of a series of cyclic and linear alkenes is described. Epoxides have been obtained in moderate to excellent conversions under mild reaction conditions through a two-step sequence, carried out in one-pot. This chemoenzymatic approach is based on a Rhizomucor miehei lipase-catalyzed perhydrolysis reaction to form the corresponding peracid, and subsequent epoxidation of the corresponding alkenes. Reaction parameters with influence in the biotransformation have been optimized specially focusing in the efficient enzymatic peracid formation by means of the correct choice of solvent, oxidant, and peracid precursor. This chemoenzymatic approach has been efficiently applied for the first time, in the regioselective chemical oxidation of (S)-carvone and limonene, both showing an opposite behavior for the oxidation of the internal and external C-C double bond, respectively.
- Méndez-Sánchez, Daniel,Ríos-Lombardía, Nicolás,Gotor, Vicente,Gotor-Fernández, Vicente
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p. 1144 - 1148
(2014/02/14)
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- Formation of naphthalene hydrates in the enzymatic conversion of 1,2-dihydronaphthalene by two fungal peroxygenases and subsequent naphthalene formation
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The formation of naphthalene hydrates (i.e. 1- and 2-hydroxy-1,2- dihydronaphthalene) displays a new activity (besides epoxidation) in the enzymatic transformation of 1,2-dihydronaphthalene by two fungal unspecific peroxygenases (UPOs) accounting for 16-19% of the overall turnover. These arene hydrates decayed into naphthalene that in turn was converted by UPOs into naphthols. The oxygen transferred during hydroxylation was shown to derive from hydrogen peroxide proving a true peroxygenation reaction.
- Kluge, Martin,Ullrich, Rene,Scheibner, Katrin,Hofrichter, Martin
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- Organocatalytic asymmetric hydrolysis of epoxides
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The hydrolytic ring opening of epoxides is an important biosynthetic transformation and is also applied industrially. We report the first organocatalytic variant of this reaction, exploiting our recently discovered activation of carboxylic acids with chiral phosphoric acids via heterodimerization. The methodology mimics the enzymatic mechanism, which involves an enzyme-bound carboxylate nucleophile. A newly designed phosphoric acid catalyst displays high stereocontrol in the desymmetrization of meso-epoxides. The methodology shows wide generality with cyclic, acylic, aromatic, and aliphatic substrates. We also apply our method in the first highly enantioselective anti-dihydroxylation of simple olefins.
- Monaco, Mattia Riccardo,Prevost, Sebastien,List, Benjamin
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supporting information
p. 8142 - 8145
(2014/08/18)
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- Activation of carboxylic acids in asymmetric organocatalysis
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Organocatalysis, catalysis using small organic molecules, has recently evolved into a general approach for asymmetric synthesis, complementing both metal catalysis and biocatalysis.1 Its success relies to a large extent upon the introduction of novel and generic activation modes.2 Remarkably though, while carboxylic acids have been used as catalyst directing groups in supramolecular transition-metal catalysis,3 a general and well-defined activation mode for this useful and abundant substance class is still lacking. Herein we propose the heterodimeric association of carboxylic acids with chiral phosphoric acid catalysts as a new activation principle for organocatalysis. This self-assembly increases both the acidity of the phosphoric acid catalyst and the reactivity of the carboxylic acid. To illustrate this principle, we apply our concept in a general and highly enantioselective catalytic aziridine-opening reaction with carboxylic acids as nucleophiles. Activation by dimerization: There is still no general activation mode for carboxylic acids in organocatalysis. The formation of heterodimers between chiral phosphoric acid diesters and carboxylic acids can be used to activate and direct reactivity of the latter in asymmetric reactions. This novel principle has been applied to the ring-opening desymmetrization and kinetic resolution of aziridines leading to valuable amino alcohols.
- Monaco, Mattia Riccardo,Poladura, Belen,Diaz De Los Bernardos, Miriam,Leutzsch, Markus,Goddard, Richard,List, Benjamin
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supporting information
p. 7063 - 7067
(2014/07/08)
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- Catalytic asymmetric synthesis of thiols
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The synthesis of enantiopure thiols is of significant interest for industrial and academic applications. However, direct asymmetric approaches to free thiols have previously been unknown. Here we describe a novel organocascade that is catalyzed by a confined chiral phosphoric acid and furnishes O-protected β-hydroxythiols with excellent enantioselectivities. The method relies on an asymmetric thiocarboxylysis of meso-epoxides, followed by an intramolecular trans-esterification reaction. By varying the reaction conditions, the intermediate thioesters can also be obtained chemoselectively and enantioselectively.
- Monaco, Mattia Riccardo,Prvost, Sbastien,List, Benjamin
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supporting information
p. 16982 - 16985
(2015/02/18)
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- Carbon Dioxide as a Protecting Group: Highly Efficient and Selective Catalytic Access to Cyclic cis-Diol Scaffolds
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The efficient and highly selective formation of a wide range of (hetero)cyclic cis-diol scaffolds using aminotriphenolate-based metal catalysts is reported. The key intermediates are cyclic carbonates, which are obtained in high yield and with high levels of diastereo- and chemoselectivity from the parent oxirane precursors and carbon dioxide. Deprotection of the carbonate structures affords synthetically useful cis-diol scaffolds with different ring sizes that incorporate various functional groups. This atom-efficient method allows the simple construction of diol synthons using inexpensive and accessible precursors and green metal catalysts and showcases the use of CO2 as a temporary protecting group. Protective Carbon: Aminotriphenolate complexes of FeIII and AlIII are highly efficient and selective catalysts for the conversion of functional (multi)cyclic oxiranes into the corresponding cis carbonates. Basic hydrolysis of the latter provides a series of useful cyclic cis-diol scaffolds in high yield. In this process, CO2 acts as both a temporary protecting group and an oxygen donor.
- Laserna, Victor,Fiorani, Giulia,Whiteoak, Christopher J.,Martin, Eddy,Escudero-Adán, Eduardo,Kleij, Arjan W.
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supporting information
p. 10416 - 10419
(2016/02/18)
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- A practical method for the synthesis of highly enantioenriched trans -1,2-amino alcohols
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A highly enantioselective addition of phenyl carbamate to meso-epoxides has been developed to efficiently generate protected trans-1,2-amino alcohols. This transformation is promoted by an oligomeric (salen)Co-OTf catalyst and has been used to prepare two useful 2-aminocycloalkanol hydrochlorides in enantiopure form on a multigram scale from commercially available starting materials.
- Birrell, James A.,Jacobsen, Eric N.
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supporting information
p. 2895 - 2897
(2013/07/26)
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- Stereoselective benzylic hydroxylation of alkylbenzenes and epoxidation of styrene derivatives catalyzed by the peroxygenase of Agrocybe aegerita
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Here we report on the stereoselective benzylic hydroxylation and C1-C2 epoxidation of alkylbenzenes and styrene derivatives, respectively, by a heme-thiolate peroxygenase (EC 1.11.2.1) from the fungus Agrocybe aegerita. Benzylic hydroxylation led exclusively to the (R)-1-phenylalkanols. For (R)-1-phenylethanol, (R)-1-phenylpropanol and (R)-1-tetralol, the ee reached >99%. For longer chain lengths, the enantiomeric excesses (ee) and total turnover numbers (TTN) decreased while the number of by-products, e.g. 1-phenylketones, increased. Epoxidation of straight chain and cyclic styrene derivatives gave a heterogeneous picture and resulted in moderate to excellent ee values and TTN: e.g., in the case of (1R,2S)-cis-β-methylstyrene oxide formation, an ee >99% and a TTN of 110000 was achieved. Hydroxylation and epoxidation were true peroxygenations, which was demonstrated by the incorporation of 18O from H218O2 into the products. The use of fed-batch devices and varying feeding strategies for the substrate and co-substrate turned out to be a suitable approach to optimize peroxygenase catalysis.
- Kluge, Martin,Ullrich, Rene,Scheibner, Katrin,Hofrichter, Martin
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supporting information; experimental part
p. 440 - 446
(2012/04/10)
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- Compounds comprising 4-benzoylpiperidine as a Sigma-1-selective ligand
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Bipiperidinyl compounds and salts thereof are disclosed. The compounds include high affinity ligands for σ1 receptors. Some compounds are also highly selective for σ1 receptor compared to σ2 receptor. Compounds can compris
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- Synthesis and in vitro biological evaluation of carbonyl group-containing inhibitors of vesicular acetylcholine transporter
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To identify selective high-affinity inhibitors of the vesicular acetylcholine transporter (VAChT), we have interposed a carbonyl group between the phenyl and piperidyl groups of the prototypical VAChT ligand vesamicol and its more potent analogues benzovesamicol and 5-aminobenzovesamicol. Of 33 compounds synthesized and tested, 6 display very high affinity for VAChT (K i, 0.25-0.66 nM) and greater than 500-fold selectivity for VAChT over σ1 and σ2 receptors. Twelve compounds have high affinity (Ki, 1.0-10 nM) and good selectivity for VAChT. Furthermore, 3 halogenated compounds, namely, trans-3-[4-(4-fluorobenzoyl) piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28b) (Ki = 2.7 nM, VAChT/sigma selectivity index = 70), trans-3-[4-(5-iodothienylcarbonyl) piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28h) (Ki = 0.66 nM, VAChT/sigma selectivity index = 294), and 5-amino-3-[4-(p-fluorobenzoyl) piperidinyl]-2-hydroxy-1,2,3,4,-tetrahydronaphthalene (30b) (Ki = 2.40 nM, VAChT/sigma selectivity index = 410) display moderate to high selectivity for VAChT. These three compounds can be synthesized with the corresponding radioisotopes so as to serve as PET/SPECT probes for imaging the VAChT in vivo.
- Efange, Simon M. N.,Khare, Anil B.,Von Hohenberg, Krystyna,MacH, Robert H.,Parsons, Stanley M.,Tu, Zhude
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experimental part
p. 2825 - 2835
(2010/08/05)
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- Synthesis and in vitro and in vivo evaluation of18F-labeled positron emission tomography (PET) ligands for imaging the vesicular acetylcholine transporter
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A new class of vesicular acetylcholine transporter inhibitor that incorporates a carbonyl group into the benzovesamicol structure was synthesized, and analogues were evaluated in vitro. (±)-trans-2-Hydroxy-3- (4-(4-[18F]fluorobenzoyl)piperidino)tetralin (9e) has Ki values of 2.70 nM for VAChT, 191 nM for σ1 and 251 nM for σ2. The racemic precursor (9d) was resolved via chiral HPLC, and (±)-[18F]9e,(-)-[18F]9e, and (+)-[ 18F]9e were respectively radiolabeled via microwave irradiation of the appropriate precursors with [18F]/F- and Kryptofix/K 2CO3 in DMSO with radiochemical yields of ~50-60% and specific activities of >2000 mCi/μmol. (-)-[18F]9e uptake in rat brain was consistent with in vivo selectivity for the VAChT with an initial uptake of 0.911 %ID/g in rat striatum and a striatum/cerebellum ratio of 1.88 at 30 min postinjection (p.i.). MicroPET imaging of macaques demonstrated a 2.1 ratio of (-)-[18F]9e in putamen versus cerebellum at 2 h p.i. (-)-[18F]9e has potential to be a PET tracer for clinical imaging of the VAChT.
- Tu, Zhude,Efange, Simon M. N.,Xu, Jinbin,Li, Shihong,Jones, Lynne A.,Parsons, Stanley M.,Mach, Robert H.
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experimental part
p. 1358 - 1369
(2009/12/26)
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- Synthesis of annulated 1,4-dioxanes and perhydro-1,4-oxazines by domino-wacker-carbonylation and domino-wacker-mizoroki-heck reactions
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Palladium(II) -catalyzed domino reactions for the formation of 1,4-dioxanes and perhydro-1,4-oxazines starting from hydroxy alkenes are described. The domino-Wacker-carbonylation comprises a Wacker oxidation, subsequent CO-insertion and a nucleophilic substitution of the intermediately formed Pd-species. The domino-Wacker-Mizoroki-Heck reaction proceeds via a Wacker oxidation, subsequent insertion into the olefinic π-bond of α,β-unsatura-ted carbonyl compounds and β-hydride elimination.
- Tietze, Lutz F.,Heins, Arne,Soleiman-Beigi, Mohammad,Raith, Christian
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experimental part
p. 1123 - 1146
(2010/10/20)
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- Catalytic asymmetric ring-opening reaction of meso-epoxides with aryl selenols and thiols catalyzed by a heterobimetallic gallium-titanium-salen complex
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A chiral heterobimetallic Lewis acid complex has been developed as an efficient catalyst. The enantioselective desymmetrization of meso-epoxides with aryl selenols and thiols catalyzed by the heterobimetallic complex has been optimized. The optically active β-arylseleno alcohols and β-hydroxy sulfides were obtained in good yields and high enantioselec- tivities (up to 97% ee and 92% ee, respectively). A strong synergistic effect between different Lewis acids was exhibited in the catalytic process. & copy; 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
- Sun, Jiangtao,Yang, Minghua,Yuan, Fang,Jia, Xuefeng,Yang, Xia,Pan, Yi,Zhu, Chengjian
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supporting information; experimental part
p. 920 - 930
(2009/11/30)
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- Synthesis of aryl-containing terpenoids based on 1,4-dihydronaphthalene
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Successive transformations including oxidation of 1,4-dihydronaphthalene into 1,2,3,4-tetrahydronaphthalen-2-one, Reformatskii reaction of the latter with methyl bromoacetate, ozonolysis of the Reformatsky reaction product, and Emmons olefination of the aldehyde group in methyl 3-oxo-5-(2-formylphenyl) pentanate thus formed gave analogs of highly active dienoate juvenoids having an aromatic ring in their molecules.
- Kukovinets,Kislitsyn,Zainullin,Mukhamedzyanova,Galin,Abdullin
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p. 362 - 368
(2008/12/22)
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- One-Pot and Stereospecific Synthesis of cis-1,2-Diazides via Mitsunobu Reaction of Epoxides
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Mitsunobu reaction of epoxides using hydrazoic acid, diethylazodicarboxylate, and triphenylphosphine as reagents gave the corresponding cis-1,2-diazides in moderate yield. Application of similar reaction conditions to trans-diols furnished the corresponding trans-1,2-diazides.
- Goeksu, Sueleyman,Secen, Hasan,Suetbeyaz, Yasar
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p. 2373 - 2378
(2007/10/03)
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- Enantiopure vic-amino alcohols and vic-diamines from (1R,2S)-1,2-dihydroxy-1,2-dihydronaphthalene
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(1S,2S)-2-Hydroxy-1-amino-1,2,3,4-tetrahydronaphthalene, (1R,2R)-1-hydroxy-2-amino-1,2,3,4-tetrahydronaphthalene, (1S,2R)-1,2-diamino-1,2,3,4-tetrahydronaphthalene, (2R,3S)-2-hydroxy-3-amino-1,2,3,4-tetrahydronaphthalene and (2S,3S)-2,3-diammino-1,2,3,4-tetrahydronaphthalene have been synthesized from (1R,2S)-1,2-dihydroxy-1,2-dihydronaphthalene. The latter was obtained, using a protocol reported in a previous paper, from naphthalene using an Escherichia coli recombinant strain containing the naphthalene dioxygenase gene cloned from Pseudomonas fluorescens N3.
- Orsini, Fulvia,Sello, Guido,Bestetti
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p. 2961 - 2969
(2007/10/03)
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- N-hydroxyalkyl derivatives of 3β-phenyltropane and 1-methylspiro[1H- indoline-3,4'-piperidine]: Vesamicol analogues with affinity for monoamine transporters
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As part of our ongoing structure-activity studies of the vesicular acetylcholine transporter ligand 2-(4-phenylpiperidino)cyclohexanol [vesamicol, 1), 22 N-hydroxy(phenyl)alkyl derivatives of 3β-phenyltropane, 6, and 1-methylspiro[1H-indoline-3,4'-piperidine], 7, were synthesized and tested for binding in vitro. Although a few compounds displayed moderately high affinity for the vesicular acetylcholine transporter, no compound was more potent than the prototypical vesicular acetylcholine transporter ligand vesamicol. However, a few derivatives of 6 displayed higher affinity for the dopamine transporter than cocaine. We conclude that modification of the piperidyl fragment of 1 will not lead to more potent vesicular acetylcholine transporter ligands.
- Efange, Simon M. N.,Kamath, Ashok P.,Khare, Anil B.,Kung, Mei-Ping,Mach, Robert H.,Parsons, Stanley M.
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p. 3905 - 3914
(2007/10/03)
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- Spirovesamicols: Conformationally restricted analogs of 2-(4- phenylpiperidino)cyclohexanol (vesamicol, AH5183) as potential modulators of presynaptic cholinergic function
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In an effort to develop selective inhibitors of vesicular acetylcholine storage, we have synthesized a series of semirigid vesamicol receptor ligands based on the structure of 2-(4-phenylpiperidino)-cyclohexanol (vesamicol, AH5183, 1). In these compounds, the planes of the phenyl and piperidyl moieties of the parent ligand 1 are held at right angles by vinyl, ethylene, and propylene bridges to form N-substituted derivatives of spiro[indene- 1,4'-piperidine], 2,3-dihydrospiro[indene-1,4'-piperidine], and 3,4- dihydrospiro[naphthalene-1(2H),4'-piperidine], respectively. Preliminary evaluation of these compounds in electric organ synaptic vesicles revealed several potent vesamicol receptor ligands, such as 1'-(2-hydroxy-1,2,3,4- tetrahydronaphth-3-yl)spiro[1H-indene-1,4'-piperidine] (11b) and 1'-(2- hydroxy-1,2,3,4-tetrahydronaphth-3-yl)spiro[2-bromo-1H-indene-1,4'- piperidine] (14), which display subnanomolar affinity for this receptor. In general, the vinyl and ethylene bridges yielded the most potent analogs while the propylene-bridged analogs were among the least potent compounds. The increased rigidity of these spiro-fused compounds, relative to the corresponding simple 4-phenylpiperidine derivatives of vesamicol, is expected to confer greater selectivity for the vesamicol receptor.
- Efange,Khare,Foulon,Akella,Parsons
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p. 2574 - 2582
(2007/10/02)
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- Naphtho and benzo analogues of the κ opioid agonist trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide
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Further elaboration on the structure-activity relationships in our U-50,488 series has revealed that benzologation of this cyclohexane-1,2-diamine derivative provides compounds which either maintain the interaction with the κ receptor (e.g. compounds 3a a
- Freeman,Michalson,D'Andrea,Baczynskyj,VonVoigtlander,Lahti,Smith,Lawson,Scahill,Mizsak,Szmuszkovicz
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p. 1891 - 1896
(2007/10/02)
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- TETRALIN DERIVATIVES
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This invention relates to novel derivatives of tetralin, to the processes for their preparation, to their use as aminopeptidase inhibitors and to their end-use application as immunomodulators and as analgesic agents.
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- Synthesis, in Vitro Acetylcholine-Storage-Blocking Activities, and Biological Properties of Derivatives and Analogues of trans-2-(4-Phenylpiperidino)cyclohexanol (Vesamicol)
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Eighty-four analogues and derivatives of the acetylcholine-storage-blocking drug trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol) were synthesized, and their potencies were evaluated with the acetylcholine active-transport assay utilizing purified synaptic vesicles from Torpedo electric organ.The parent drug exhibits enantioselectivity, with (-)-vesamicol being 25-fold more potent than (+)-vesamicol.The atomic structure and absolute configuration of (+)-vesamicol were determined by X-ray crystallography.The absolute configuration of (-)-vesamicol is 1R,2R.Structure-activity evidence indicates that (-)-vesamicol does not act as an acetylcholine analogue.Alterations to all three rings can have large effects on potency.Unexpectedly, analogues locking the alcohol and ammonium groups trans-diequatorial or trans-diaxial both exhibit good potency.A potent benzovesamicol family has been discovered that is suitable for facile elaboration of the sort useful in affinity labeling and affinity chromatography applications.A good correlation was found between potencies as assessed by the acetylcholine transport assay and LD50 values in mouse.
- Rogers, Gary A.,Parsons, Stanley M.,Anderson, D. C.,Nilsson, Lena M.,Bahr, Ben A.,et al.
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p. 1217 - 1230
(2007/10/02)
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- Benoz-fused cycloalkane trans-1,2-diamine derivatives
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Benzo-fused cycloalkane and oxa- and thia-cycloalkane trans-1,2-diamine compounds of the formula: STR1 wherein A, B, C, D, n, X, Y, R, R1, R2 and R3 are as defined in the specification, e.g., trans-3,4-dichloro-N-methyl-N-
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- Oxidation of Alkyl Phenyl Selenides, Tellurides, and Telluroxides with meta-Chloroperbenzoic Acid for a Facile and Novel Transformation of C-Se and C-Te Bonds to C-O Bonds
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In sharp contrast to the well-known selenoxide elimination leading to olefins, the treatment of alkyl phenyl selenides (PhSeR) with an excess of meta-chloroperbenzoic acid (MCPBA; 2-5 equiv. to a selenide) in alcohol at room temperature affords the corresponding dialkyl ethers by the substitution of a phenylselenium (PhSe) moiety with an alkoxy group.A similar reaction proceeds by using alkyl phenyl tellurides (PhTeR) and telluroxides , a facile substitution of PhTe or PhTe(O) moiety by an alkoxy group being observed.Methanol is the most appropriate solvent for these oxidations and alkyl methyl ethers are formed in excellent yields.The reaction is accompanied by phenyl migration when applied to some selenides, tellurides, and telluroxides having a phenyl group at a vicinal position to the PhSe, PhTe, or PhTe(O) moiety.Application to the methoxyselenation and methoxytelluration products of cyclohexene and cycloheptene results in a ring-contraction to afford the dimethyl acetals of cyclopentane- and cyclohexane-carbaldehyde, respectively.In case of an allylic phenyl selenide, a sigmatropic rearrangement giving a rearranged allylic alcohol occurs in much preference to the substitution by the methoxy group.Other oxidizing agents than MCPBA such as NaIO4, H2O2, t-BuOOH, and ozone are generally ineffective under similar conditions.It is proposed that the reaction mainly takes place as follows.Alkyl phenyl selenone, alkyl phenyl tellurone, or the MCPBA addition product to them is formed as a reactive intermediate in which an alkyl C-Se or alkyl C-Te bond fission occurs heterolytically by a nucleophilic attack of alcohol, sometimes accompanied by a 1,2-shift of the β-substituent, i.e., phenyl migration and ring-contraction.
- Uemura, Sakae,Fukuzawa, Shin-ichi
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p. 471 - 480
(2007/10/02)
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- Photo-induced Reactions of Some Epoxides in Isopropanol: Effect of Structural Parameters on Photoreduction and Photosolvolysis
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Competing photoreduction and photosolvolysis reactions have been observed in the photolysis of a number of epoxides (1-8).Certain epoxides display extreme photobehaviour; photosolvolysis is the exclusive process in 5 and 7 whereas 8 undergoes only photoreduction.A novel photo-Wagner-Meerwein rearrangement occurs in the photosolvolysis of benzonorbornene epoxide (7).Mechanisms involving radical and ionic intermediates are discussed.
- Sonawane, H. R.,Sethi, S. C.,Merchant, S. N.
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p. 934 - 939
(2007/10/02)
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- Hypotensive perhydro naphthalene pentol derivatives
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Compounds are provided having the structure STR1 wherein R1, R2, R3 or R4 is hydrogen or acyl and R5 is hydrogen or acyl, X is a straight or branched bivalent alkylene radical and Y is STR2 These compounds are useful in the treatment of hypertension.
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- 5,6,7,8-Tetrahydronaphthalene hypotensive agents
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5,6,7,8-Tetrahydronaphthalenes having the structure STR1 and the pharmaceutically acceptable salts thereof, are useful as blood pressure lowering agents. In the above formula R1 can be hydrogen or alkyl; R2 is alkyl; R3 an
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