- 3- and 4-Substituted 4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as potassium channel openers: Synthesis, pharmacological evaluation, and structure-activity relationships
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4-N-Subsituted and -unsubstituted 3-alkyl- and 3-(alkylamino)-4H- pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested vs diazoxide and selected 3-alkyl- and 3-(alkylamino)-7-chloro-4H-1,2,4- benzothiadiazine 1,1-dioxides as potassium channel openers on pancreatic and vascular tissues. Several 4-N-unsubstituted 3-(alkylamino)pyridothiadiazines and some 3-(alkylamino)-7-chlorobenzothiadiazines were found to be more potent than diazoxide for the inhibition of the insulin-releasing process. Moreover, the 3-(alkylamino)pyridothiadiazines appeared to be more selective for the pancreatic than for the vascular tissue. By means of the pharmacological results obtained on pancreatic B-cells, structure-activity relationships were deduced and a pharmacophoric model for the interaction of these drugs with their receptor site associated to the pancreatic K(ATP) channel was proposed. According to their selectivity for the B-cell (endocrine tissue) vs the vascular (smooth muscle tissue) ionic channel, selected 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides may serve as pharmacological tools in studying the K(ATP) channels ('pancreatic- like' K(ATP) channels) in other tissues.
- De Tullio,Pirotte,Lebrun,Fontaine,Dupont,Antoine -,Ouedraogo,Khelili,Maggetto,Masereel,Diouf,Podona,Delarge
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- Separate Sets of Mutations Enhance Activity and Substrate Scope of Amine Dehydrogenase
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Mutations were introduced into the leucine amine dehydrogenase (L-AmDH) derived from G. stearothermophilus leucine dehydrogenase (LeuDH) with the goals of increased activity and expanded substrate acceptance. A triple variant (L-AmDH-TV) including D32A, F101S, and C290V showed an average of 2.5-fold higher activity toward aliphatic ketones and an 8.0 °C increase in melting temperature. L-AmDH-TV did not show significant changes in relative activity for different substrates. In contrast, L39A, L39G, A112G, and T133G in varied combinations added to L-AmDH-TV changed the shape of the substrate binding pocket. L-AmDH-TV was not active on ketones larger than 2-hexanone. L39A and L39G enabled activity for straight-chain ketones as large as 2-decanone and in combination with A112G enabled activity toward longer branched ketones including 5-methyl-2-octanone.
- Franklin, Robert D.,Mount, Conner J.,Bommarius, Bettina R.,Bommarius, Andreas S.
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p. 2436 - 2439
(2020/04/16)
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- An Ammonium-Formate-Driven Trienzymatic Cascade for ω-Transaminase-Catalyzed (R)-Selective Amination
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(R)-Amination mediated by (R)-specific ω-transaminases generally requires costly d-alanine in excess to obtain the desired chiral amines in high yield. Herein, a one-pot, trienzymatic cascade comprising an (R)-specific ω-transaminase, an amine dehydrogenase, and a formate dehydrogenase was developed for the economical and eco-friendly synthesis of (R)-chiral amines. Using inexpensive ammonium formate as the sole sacrificial agent, the established cascade system enabled efficient ω-transaminase-mediated (R)-amination of various ketones, with high conversions and excellent ee (>99%); water and CO2 were the only waste products.
- Chen, Fei-Fei,Liu, Lei,Wu, Jian-Ping,Xu, Jian-He,Zhang, Yu-Hui,Zhang, Zhi-Jun,Zheng, Gao-Wei
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p. 14987 - 14993
(2019/12/02)
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- (R)- SELECTIVE AMINATION
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The present invention relates to a method for the enzymatic synthesis of enantiomerically enriched (R)-amines of general formula [1][c] from the corresponding ketones of the general formula [1][a] by using novel transaminases. These novel transaminases are selected from two different groups: either from a group of some 20 proteins with sequences as specified herein, or from a group of proteins having transaminase activity and isolated from a microorganism selected from the group of organisms consisting of Rahnella aquatilis, Ochrobactrum anthropi, Ochrobactrum tritici, Sinorhizobium morelense, Curtobacterium pusiffium, Paecilomyces lilacinus, Microbacterium ginsengisoli, Microbacterium trichothecenolyticum, Pseudomonas citronellolis, Yersinia kristensenii, Achromobacter spanius, Achromobacter insolitus, Mycobacterium fortuitum, Mycobacterium frederiksbergense, Mycobacterium sacrum, Mycobacterium fluoranthenivorans, Burkhoideria sp., Burkhoideria tropica, Cosmospora episphaeria, and Fusarium oxysporum.
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Paragraph 0120; 0121; 0122
(2016/03/22)
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- Asymmetric Amination of Secondary Alcohols by using a Redox-Neutral Two-Enzyme Cascade
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Multienzyme cascade approaches for the synthesis of optically pure molecules from simple achiral compounds are desired. Herein, a cofactor self-sufficient cascade protocol for the asymmetric amination of racemic secondary alcohols to the corresponding chiral amines was successfully constructed by employing an alcohol dehydrogenase and a newly developed amine dehydrogenase. The compatibility and the identical cofactor dependence of the two enzymes led to an ingenious in situ cofactor recycling system in the one-pot synthesis. The artificial redox-neutral cascade process allowed the transformation of racemic secondary alcohols into enantiopure amines with considerable conversions (up to 94 %) and >99 % enantiomeric excess at the expense of only ammonia; this method thus represents a concise and efficient route for the asymmetric synthesis of chiral amines. If you know what amine: A redox-neutral two-enzyme cascade encompassing an alcohol dehydrogenase (ADH) and an amine dehydrogenase (AmDH) is constructed for the synthesis of chiral amines from the corresponding racemic alcohols in one pot to afford considerable conversions (up to 94 %) and high enantiomeric excess values (>99 %) at the expense of only ammonia.
- Chen, Fei-Fei,Liu, You-Yan,Zheng, Gao-Wei,Xu, Jian-He
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p. 3838 - 3841
(2016/01/26)
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- A novel chimeric amine dehydrogenase shows altered substrate specificity compared to its parent enzymes
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We created a novel chimeric amine dehydrogenase (AmDH) via domain shuffling of two parent AmDHs ('L- and F-AmDH'), which in turn had been generated from leucine and phenylalanine DH, respectively. Unlike the parent proteins, the chimeric AmDH ('cFL-AmDH') catalyzes the amination of acetophenone to (R)-methylbenzylamine and adamantylmethylketone to adamantylethylamine.
- Bommarius, Bettina R.,Schürmann, Martin,Bommarius, Andreas S.
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p. 14953 - 14955
(2015/02/19)
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- Microwave-Enhanced Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)imines
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Microwave irradiation has considerably enhanced the efficiency of the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)imines in isopropyl alcohol catalyzed by a ruthenium complex bearing the achiral ligand 2-amino-2-methylpropan-1-ol. In addition to shortening reaction times for the transfer hydrogenation processes to only 30 min, the amounts of ruthenium catalyst and isopropyl alcohol can be considerably reduced in comparison with our previous procedure assisted by conventional heating, which diminishes the environmental impact of this new protocol. This methodology can be applied to aromatic, heteroaromatic and aliphatic N-(tert-butylsulfinyl)ketimines, leading, after desulfinylation, to the expected primary amines in excellent yields and with enantiomeric excesses of up to 96 %. Microwave irradiation promotes the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)imines in 2-propanol catalysed by a ruthenium complex bearing an achiral β-amino alcohol as ligand. After desulfinylation, α-branched primary amines containing aromatic, heteroaromatic and aliphatic substituents are obtained in excellent yields and with enantiomeric excesses of up to 96 %.
- Pablo, Oscar,Guijarro, David,Yus, Miguel
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p. 7034 - 7038
(2016/02/19)
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- Optically active amines by enzyme-catalyzed kinetic resolution
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Chiral amines are resolved by an enzyme-catalyzed kinetic resolution. Key steps are the selective acylation of one enantiomer with isopropyl methoxyacetate, separation of the resulting amide from the unreacted antipode, and finally amide hydrolysis. The p
- Ditrich, Klaus
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experimental part
p. 2283 - 2287
(2009/04/06)
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- Low-temperature deacylation of N-monosubstituted amides
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(Chemical Equation Presented) The (PhO)3P-Cl2 reagent, prepared in situ by titrating a solution of triphenyl phosphite with chlorine, is used to convert N-monosubstituted amides into their corresponding amines. The reaction, if compared to other traditional methods, shows the advantage of very mild conditions and low temperature (-30°C→rt).
- Spaggiari, Alberto,Blaszczak, Larry C.,Prati, Fabio
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p. 3885 - 3888
(2007/10/03)
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- Method of inhibiting or treating chemotherapy-induced hair loss
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A method for inhibiting hair loss and/or promoting hair growth in chemotherapy and/or radiation therapy patients wherein the (R)-enantiomer of 4-[[(cyanoimino)-[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile is administered prior to, simultaneous with and/or after chemotherapy and/or radiation treatment.
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- Influence of bulky substituents on histamine H3 receptor agonist/antagonist properties
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Novel derivatives of 3-(1H-imidazol-4-yl)propanol were designed on the basis of lead compounds belonging to the carbamate or ether series possessing (partial) agonist properties on screening assays of the histamine H3 receptor. One pair of enantiomers in the series of α-methyl-branched chiral carbamates was stereoselectively prepared in high optical yields. Enantiomeric purity was checked by Mosher amide derivatives of precursors and capillary electrophoresis of the final compounds with trimethyl-β-cyclodextrin as chiral selector, and was determined to be ≥95%. The novel compounds were investigated in various histamine H3 receptor assays in vitro and in vivo. Some compounds displayed partial agonist activity on synaptosomes of rat brain cortex, whereas others exhibited antagonist properties only. Selected compounds were investigated in [125I]iodoproxyfan binding studies on the human histamine H3 receptor and showed high affinity in the nanomolar concentration range. Under in vivo conditions after oral administration to mice, some of the compounds exhibited partial or full agonist activity in the brain at low dosages. The (S)-enantiomer of one pair of chiral carbamates (9) proved to be the eutomer; thus, the (S)-enantiomer was selected for further pharmacological studies. In a peripheral in vivo test model in rats, measuring the level of inhibition of capsaicin-induced plasma extravasation, (S)-9 again proved its high oral agonist potency with full intrinsic activity (ED50 values of 0.07-0.1 mg/kg depending on tissue).
- Sasse, Astrid,Ligneau, Xavier,Rouleau, Agnès,Elz, Sigurd,Ganellin, C. Robin,Arrang, Jean-Michel,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
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p. 4000 - 4010
(2007/10/03)
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- Catalytic Leuckart-Wallach-type reductive amination of ketones
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A Cp*Rh(III) complex catalyzes reductive amination of ketones using HCOONH4 at 50-70°C to give the corresponding primary amines in high yields. The reaction is clean and operationally simple and proceeds at a lower temperature and with higher chemoselectivity than the original Leuckart-Wallach reaction. The new method has been applied to the synthesis of α-amino acids directly from α-keto acids.
- Kitamura, Masato,Lee, Donghyun,Hayashi, Shinnosuke,Tanaka, Shinji,Yoshimura, Masahiro
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p. 8685 - 8687
(2007/10/03)
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- Method for inhibiting or treating chemotherapy-induced hair loss
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A method for inhibiting hair loss and/or promoting hair growth in chemotherapy and/or radiation therapy patients wherein the (R)-enantiomer of 4-[[(cyanoimino)-[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile is administered prior to, simultaneous with and/or after chemotherapy and/or radiation treatment.
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- Synthesis of 2-aminoquinazoline-4(3H)-one derivatives as potential potassium channel openers
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Starting from 2-thioxoquinazolin-4-one, the synthesis of 2-amino-4(3H)- one derivatives, structurally related to potassium channels openers pinacidil and diazoxide, is described.
- Erb, Benedicte,Akue, Rufine,Rigo, Benoit,Pirotte, Bernard,Couturier, Daniel
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p. 253 - 260
(2007/10/03)
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- Enantiomers of 4-[[(cyanoimino) [(1,2,2-trimethylpropyl) amino]methyl]amino]benzonitrile
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The (R)-enantiomer of 4-[[(cyanoimino)[(1,2,2-trimethylpropyl)amino]methyl]amino]benzonitrile as well as the corresponding (S)-enantiomer are useful for promoting hair growth such as in male pattern baldness.
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- Asymmetric addition of alkyllithium to chiral imines: α-Naphthylethyl group as a chiral auxiliary
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The diastereoselective nucleophilic addition of alkyllithium to N- alkylidene-α-naphthylethylamine was carried out. In the presence of Lewis acids or Lewis bases, organolithiums reacted smoothly with imines to give the corresponding amines in high stereoselectivity (up to 100% de). Furthermore, the resulting optically active amines were found to be useful for asymmetric reactions as chiral ligands.
- Yamada, Hideki,Kawate, Tomohiko,Nishida, Atsushi,Nakagawa, Masako
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p. 8821 - 8828
(2007/10/03)
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- Structure-activity studies of potassium channel opening in pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas
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Potassium channel opening activity for pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas, has been assessed through simultaneous measurement of spontaneous contractile activity and stimulation of 86Rb+ efflux from rat portal veins loaded with 86Rb+. The good correlation between these two effects suggests that the vasodilator activity of the compounds is directly attributable to an increased opening of potassium channels. The resulting quantitative in vitro data has been used to analyze the structure-activity relationships for potassium channel opening, allowing the biological activity to be rationalized in terms of a pharmacophore involving a hydrogen-bond-acceptor element, a hydrogen-bond- donor element, and a lipophilic binding group. A model for the binding of pinacidil-related compounds to their potassium channel receptor has been developed, and compounds designed to test this model have been synthesized and tested. Prototropic equilibria are implicated as playing a fundamental role in determining the hydrogen-bonding ability of the compounds, and conformational changes in the receptor are invoked to explain disparities in the chiral recognition of lipophilic groups in different compounds.
- Manley,Quast
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p. 2327 - 2340
(2007/10/02)
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- Branched amides of L-aspartyl-D-amino acid dipeptides
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Amides of L-aspartyl-D-amino acid dipeptides of the formula STR1 and physiologically acceptable cationic and acid addition salts thereof wherein Ra is CH2 OH or CH2 OCH3 ; R is a branched member selected from the group consisting of fenchyl, diisopropylcarbinyl, d-methyl-t-butylcarbinyl, d-ethyl-t-butylcarbinyl, di-t-butylcarbinyl, 2-methylthio-2,4-dimethylpentan-3-yl, STR2 where at least one of R3, R4, R5, R6 is alkyl having from one to four carbon atoms and the remainder are hydrogen or alkyl having from one to four carbon atoms, X is O, S, SO, SO2, C=O or CHOH; m is zero or 1-4, n and p are each zero, 1, 2 or 3 where the sum of n+p is not greater than 3 and the sum of the carbon atoms in R3, R4, R5 and R6 is not greater than six, and when both of R3 and R4 or R5 and R6 are alkyl they are methyl or ethyl, STR3 where one of R7, R8, R9 is alkyl having from one to four carbon atoms and the remainder are hydrogen or alkyl having from one to four carbon atoms and the sum of the carbon atoms in R7, R8 and R9 is not greater than six, m and q are the same or different and each have the values previously defined for m; STR4 where each of R12 and R13 are methyl or ethyl, or R12 is hydrogen and R13 is alkyl having from one to four carbon atoms, Z is O or NH and t is 1 or 2, STR5 where W is 1-4, R14 and R16 are each alkyl having from one to four carbon atoms, R15 is H, OH, methyl or ethyl and the sum of the carbon atoms in R14, R15 and R16 is not greater than six and when both of R14 and R15 are alkyl they are methyl or ethyl, and STR6 where R17 and R19 are alkyl having from one to four carbon atoms, R18 and R20 are H or alkyl having one to two carbon atoms, A is OH and B is H, OH or CH3 and taken together A and B are STR7 where the sum of the carbon atoms in R17, R18, R19 and R20 is not greater than six and when both of R17 and R18 or R19 and R20 are alkyl they are methyl or ethyl; said amides are potent sweeteners having advantages over the prior art, edible compositions containing them, methods for their use in edible compositions and novel amide intermediates useful in their production.
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- Configurational Prevalence at the Nitrogen Atom in Chiral, Open Chain, Secondary Amines
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The stereochemistry of chiral, open chain, secondary amines has been studied by means of low-temperature (1)H and (13)C n.m.r. spectroscopy and by PCILO molecular-orbital calculations.The chiral nitrogen assumes a strongly prevalent configuration under the assymmetric induction of a vicinal asymmetric carbon atom.In the most probable conformation of the secondary amine the lone pair of the nitrogen is placed in the most crowded position.
- Salvadori, Piero,Rosini, Carlo,Lazzaroni, Raffaello,Pini, Dario
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p. 1919 - 1922
(2007/10/02)
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