- Cysteine Isocyanide in Multicomponent Reaction: Synthesis of Peptido-Mimetic 1,3-Azoles
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An alternative approach toward the simple and robust synthesis of highly substituted peptidic thiazole derivatives using Ugi-multicomponent reaction (U-MCR) is described. Thus, we introduced the enantiopure (R)-2-methyl-2-isocyano-3-(tritylthio)propanoate as a novel class of isocyanide in MCR. This bifunctional isocyanide was found to undergo mild cyclodehydration to afford thiazole containing peptidomimetics in a short synthetic sequence. Several examples of bis-heterocyclic rings were also synthesized through the proper choice of the aldehyde component in the U-4CR. The method opens a wide range of applications toward the synthesis of nonribosomal natural products and other bioactive compounds.
- Vishwanatha, Thimmalapura M.,Kurpiewska, Katarzyna,Kalinowska-Tlu?cik, Justyna,D?mling, Alexander
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- Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly Convergent Multicomponent Assembly
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A concise and modular total synthesis of the highly potent N14-desacetoxytubulysin H (1) has been accomplished in 18 steps in an overall yield of up to 30percent. Our work highlights the complexity-augmenting and route-shortening power of diastereoselective multicomponent reaction (MCR) as well as the role of bulky ligands to perfectly control both the regioselective and diastereoselective synthesis of tubuphenylalanine in just two steps. The total synthesis not only provides an operationally simple and step economy but will also stimulate major advances in the development of new tubulysin analogues.
- Vishwanatha, Thimmalapura M.,Giepmans, Ben,Goda, Sayed K.,D?mling, Alexander
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- Synthesis and luminescence properties of biphenyl-type firefly luciferin analogs with a new, near-infrared light-emitting bioluminophore
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New firefly luciferin analogs of the 4,4′-substituted biphenyl-type were synthesized. One analog with a 4′-dimethylamino group possessed bioluminescence activity, emitting near-infrared biological window light at 675 nm suitable for deep-site bioimaging of living animals. The chemiluminescence light-emission maximum of the corresponding methyl ester of the bioluminescence active analog was 500 nm, implying that biphenyl and thiazolinone rings in the light emitter might be placed in a coplanar conformation at the polar luciferase active site.
- Miura, Chihiro,Kiyama, Masahiro,Iwano, Satoshi,Ito, Kazuto,Obata, Rika,Hirano, Takashi,Maki, Shojiro,Niwa, Haruki
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- Intramolecular hydrogen-bonding activation in cysteines: A new effective radical scavenger
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The challenge of developing organic molecules with improved antioxidant activities for a competitive marketplace requires, given the great amount of possibilities, much laboratory work. Nowadays, the ability of methodologies based on quantum chemistry to determine the influence of different modifications on a molecule core provides a powerful tool for selecting the most useful derivatives to be synthesized. Here, we report the results of the assessment of antioxidant activity for quaternary amino acids, specifically for cysteine derivatives. The effect of introducing different substituents on the cysteine core is evaluated by using DFT to obtain an adequate structure-antioxidant activity relationship. This theoretical study shows a small panel of targets among which (R)-N-acetyl-2-methylcysteine methyl ester 15 exhibits special features and relevant antioxidant activity. The conformational 1H NMR study of this synthesized compound indicates the existence of an intramolecular C7 member ring involving S-H?OC substructure, which is reported for the first time in the literature for this amino acid unit. This unusual conformation seems to be the reason for the high antioxidant capacity experimentally found for this compound.
- Haya, Luisa,Osante, I?aki,Mainar, Ana M.,Cativiela, Carlos,Urieta, Jose S.
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- Synthesis and stereochemistry of (?)-FE399
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The stereochemistry of selective anticancer compound FE399 was determined to be rel-9R,14R,17R by theoretical and synthetic studies. Relative stereochemistry of FE399 was predicted by comparison of the 13C NMR chemical shifts of the natural sample with that predicted by theoretical calculation for each possible stereoisomer. The first synthesis of (9R,14R,17R)-(?)-FE399 was achieved using an amide formation of a dithiazocane with a hydroxy dodecanoic acid derivatives and sixteen-membered macrolactonization as key steps. The overall yield was 18% in ten steps from L-cysteine and (S)-glycidyl tosylate.
- Ishigami, Ken,Katsuta, Ryo,Kimura, Kenji,Masada, Naoko,Nukada, Tomoo,Yajima, Arata
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Read Online
- Oxidative peptide bond formation of glycine-amino acid using 2-(aminomethyl)malononitrile as a glycine unit
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Amide linkage of glycine-amino acid was synthesized by coupling of substituted 2-(aminomethyl)malononitrile as a C-terminal glycine unit and N-terminal amine using CsOAc and O2in an aqueous solution. This is a coupling reagent-free and catalyst-free peptide synthesisviaoxidative amide bond formation. Various tripeptides and tetrapeptides were synthesized efficiently and the sulfide moiety is inert even under an oxygen atmosphere.
- Wang, Xiaoling,Li, Jing,Hayashi, Yujiro
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p. 4283 - 4286
(2021/05/05)
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- Structurally Diverse Acyl Bicyclobutanes: Valuable Strained Electrophiles
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Bicyclo[1.1.0]butanes (BCBs) are highly strained carbocycles that have emerged as versatile synthetic tools, particularly for the construction of functionalized small molecules. This work reports two efficient pathways for the rapid preparation of over 20 structurally diverse BCB ketones, encompassing simple alkyl and aryl derivatives, as well as unprecedented amino acid, dipeptide, bioisostere, and bifunctional linchpin reagents currently inaccessible using literature methods. Analogues are readily forged in two steps and in high yields from simple carboxylic acids or through unsymmetrical ketone synthesis beginning with a convenient carbonyl dication equivalent. The utility of this novel toolbox of strained electrophiles for the selective modification of proteinogenic nucleophiles is highlighted.
- Attard, Riley H.,Gardiner, Michael G.,Malins, Lara R.,Schwartz, Brett D.,Zhang, Meng Yao
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p. 2808 - 2812
(2020/03/04)
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- TUBULYSIN DERIVATIVES AND METHODS FOR PREPARING THE SAME
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The invention relates to novel means and methods for the synthesis of tubulysin and derivatives thereof, which find their use e.g. as cytotoxic agents in targeted drug delivery. Provided is a method for preparing a tubulysin derivative, comprising reacting compounds A, B and C in a 3- component Passerini reaction, wherein compound A is a carboxylic acid according to the general formula (A); wherein compound B is an aldehyde according to the general formula (B); and wherein compound C is an isocyanide according to the general formula (C).
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Page/Page column 26; 27
(2020/02/16)
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- Method for synthesizing impurity isomers of bupropion hydrochloride sustained-release tablets and application of impurity isomers
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The invention discloses a method for synthesizing impurity enantiomers of bupropion hydrochloride, and belongs to the field of pharmaceutical and chemical engineering. The method includes carrying out mercapto protection, condensation and de-protection cyclization consecutive reaction on D-cysteine methyl ester hydrochloride (a compound I) which is used as a starting material; separating and hydrolyzing isomers by means of column chromatography to obtain (3S, 5S, 6S)-6-(3-chlorphenyl)-6-hydroxyl-5-methyl thiomorpholine-3-carboxylic acid and (3S, 5R, 6R)-6-(3-chlorphenyl)-6-hydroxyl-5-methyl thiomorpholine-3-carboxylic acid. The method has the advantages of concise and efficient synthetic route, stereospecific chiral control, high reaction yield and inexpensive and easily available materials, solvents and reagents. Besides, the impurity enantiomers can be used for controlling the quality of bupropion hydrochloride sustained-release tablets or can be used as impurity reference substances.
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Paragraph 0055
(2017/11/01)
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- Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics
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A general strategy is introduced for the efficient synthetic access of disulfide linked artificial macrocycles via a Ugi four-component reaction (U4CR) followed by oxidative cyclization. The double-mercapto input is proposed for use in the Ugi reaction, thereby yielding all six topologically possible combinations. The protocol is convergent and short and enables the production of novel disulfide peptidomimetics in a highly general fashion.
- Vishwanatha, Thimmalapura M.,Bergamaschi, Enrico,D?mling, Alexander
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supporting information
p. 3195 - 3198
(2017/06/23)
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- New hydrogen halide salt
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PROBLEM TO BE SOLVED: To provide novel substances excellent in water solubility and available as luminescent substrates in firefly bioluminescent systems.SOLUTION: There are provided hydrogen halide salts of compounds represented by the specified general formula (I) or the specified general formula (II).
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Paragraph 0048
(2017/01/31)
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- Polypeptide Immobilization
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The present invention provides a method, comprising (a) providing a reactant ligand attached to a substrate; (b) contacting the substrate with a fusion polypeptide, said fusion polypeptide comprising a capture polypeptide fused to a display polypeptide un
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- LUMINESCENT SUBSTRATE FOR LUCIFERASE
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[Problem] It is an object of the present invention to provide a firefly luciferin and firefly luciferin analog that are modified to maintain luminescent activity by luciferase in a firefly bioluminescent system. In particular, it is an object of the present invention to provide a new luminescent substrate for which the emission wavelength in a firefly bioluminescent system is shifted to a longer wavelength than that of a conventional luminescent substrate. [Solution] The present invention provides a luciferin in which the benzothiazole ring moiety has been modified at the 7-position, a luciferin analog in which the benzene ring moiety has been modified at the 6-position, and a luciferin analog in which the 6-(dialkylamino)-2-naphthalenyl moiety has been modified at the 5-position.
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Paragraph 0111-0112; 0130-0132
(2014/07/23)
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- Development of simple firefly luciferin analogs emitting blue, green, red, and near-infrared biological window light
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Simple firefly luciferin analogs emitting blue, green, and red light were developed. The longest emission maximum was observed at 675 nm, which belongs to the NIR biological window (650-900 nm), useful for deep site bioimaging of living animals. The analogs showed a slow rise of emission intensity compared with the rapid emission of natural luciferin. The light emission of the adenylated analogs was strongly enhanced compared with those of analogs themselves.
- Iwano, Satoshi,Obata, Rika,Miura, Chihiro,Kiyama, Masahiro,Hama, Kazutoshi,Nakamura, Mitsuhiro,Amano, Yoshiharu,Kojima, Satoshi,Hirano, Takashi,Maki, Shojiro,Niwa, Haruki
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p. 3847 - 3856
(2013/07/04)
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- Development of a new enzyme-responsive self-immolative spacer conjugate applicable to the controlled drug release
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A new self-immolative spacer conjugate based on a chemical adaptor unit aiming at controlled releasing drugs was designed and synthesized. It releases a fluorophore which was used as a model drug via a spontaneous cyclization mechanism after cleavage of an enzyme substrate. This system was proved to be stable under physiological conditions and only decomposed triggered by enzyme. It provides a generic linkage allowing connection of a variety of drugs and targeted devices to the chemical adaptor.
- Jin, Hui-Juan,Lu, Jing,Wu, Xue
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experimental part
p. 3465 - 3469
(2012/08/08)
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- Novel molecular combination deriving from natural aminoacids and polyphenols: Design, synthesis and free-radical scavenging activities
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Following the recent output of scientific publications in the matter of synergic activity between different antioxidants, we have undertaken the present study with the aim to synthesize new molecules with radical-scavengers activity based on the conjugation of bioactive portions (i.e. phenols, cysteine, methionine or tyrosine), characterized by different structures and mechanisms of action, to promote the simultaneous quenching of different radical species in the site of the oxidative damage. In this context, derivatives of phenolic acid, aminoacids and dopamine have been also prepared. The newly synthesized compounds were evaluated in vitro applying specific and complementary antioxidant test such as DPPH assay and ORAC test. As emerged from the evaluation, prerequisites for the activity of the synthesized molecules were: i) the maintenance of at least two hydroxylic groups on the aromatic moiety of phenolic portion, ii) the presence of a spacer between the aromatic moiety and the carbonilic group.
- Silvia, Vertuani,Baldisserotto, Anna,Scalambra, Emanuela,Malisardi, Gemma,Durini, Elisa,Manfredini, Stefano
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experimental part
p. 383 - 392
(2012/07/28)
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- Dipeptide-based models of nickel superoxide dismutase: Solvent effects highlight a critical role to Ni-S bonding and active site stabilization
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Nickel superoxide dismutase (Ni-SOD) catalyzes the disproportionation of the superoxide radical to O2 and H2O2 utilizing the Ni(III/II) redox couple. The Ni center in Ni-SOD resides in an unusual coordination environment that is distinct from other SODs. In the reduced state (Ni-SODred), Ni(II) is ligated to a primary amine-N from His1, anionic carboxamido-N/thiolato-S from Cys2, and a second thiolato-S from Cys6 to complete a NiN2S2 square-planar coordination motif. Utilizing the dipeptide N2S2- ligand, H 2N-Gly-l-Cys-OMe (GC-OMeH2), an accurate model of the structural and electronic contributions provided by His1 and Cys2 in Ni-SOD red, we constructed the dinuclear sulfur-bridged metallosynthon, [Ni2(GC-OMe)2] (1). From 1 we prepared the following monomeric Ni(II)-N2S2 complexes: K[Ni(GC-OMe)(SC 6H4-p-Cl)] (2), K[Ni(GC-OMe)(StBu)] (3), K[Ni(GC-OMe)(SC6H4-p-OMe)] (4), and K[Ni(GC-OMe)(SNAc)] (5). The design strategy in utilizing GC-OMe2- is analogous to one which we reported before (see Inorg. Chem.2009, 48, 5620 and Inorg. Chem. 2010, 49, 7080) where Ni-SODred active site mimics can be assembled at will with electronically variant RS- ligands. Discussed herein is our initial account pertaining to the aqueous behavior of isolable, small-molecule Ni-SOD model complexes (non-maquette based). Spectroscopic (FTIR, UV-vis, ESI-MS, XAS) and electrochemical (CV) measurements suggest that 2-5 successfully simulate many of the electronic features of Ni-SODred. Furthermore, the aqueous studies reveal a dynamic behavior with regard to RS- lability and bridging interactions, suggesting a stabilizing role brought about by the protein architecture.
- Gale, Eric M.,Cowart, Darin M.,Scott, Robert A.,Harrop, Todd C.
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experimental part
p. 10460 - 10471
(2011/12/03)
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- Synthesis and electrochemical studies of disubstituted ferrocene/dipeptide conjugates with sulfur-containing side chains
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A series of 1 1'-disubstituted ferrocenoyl peptides incorporating dipeptide sidearms has been synthesized and studied electrochemically. The target peptides include ferrocene as an electrochemical reporter, sulfur-containing amino acids (L-methionine, S-methyl-L-cysteine, S-trityl-L-cysteine, S-benzhydryl-L- cysteine) as metal binding agents, and amino acids with non-polar side chains (L-alanine, L-valine, L-phenylalanine) as spacers between reporter and metal binding groups. Ferrocene/dipeptide conjugates were prepared using solution phase peptide synthesis methods employing a BOC-protecting group strategy and HBTU- (O-(benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate) mediated peptide coupling. The electrochemical properties of these 1, 1'-substituted ferrocenoyl peptides have been characterized using cyclic voltammetry. All exhibit fully reversible one electron oxidation steps; forward sweep half wave peaks (EF), reverse sweep half wave peaks (ER), peak separations (DEP) and half wave potentials (E1/2) are reported. Finally, towards the goal of utilizing ferrocenoyl peptides to detect heavy metals in solution, the response of these ferrocene/dipeptide conjugates to metal cations (zinc(II), mercury(II), cadmium(II), lead(II), silver(I)) has been examined. Monitoring changes in the potential of the Fe(II)/Fe(III) redox couple to follow peptide/metal interactions, we have probed the influence of the spacer unit between the redox reporter and the metal-binding amino acid, and shown that these systems respond to mercury(II) more strongly than to other heavy metal ions.
- Scully, Conor C.G.,Rutledge, Peter J.
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scheme or table
p. 5653 - 5659
(2010/10/02)
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- AZAINDAZOLE COMPOUNDS AS CCR1 RECEPTOR ANTAGONISTS
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Disclosed are compounds of the formula (I), useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of CCR1 including autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Also disclosed are methods of making and methods of using same.
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Page/Page column 195; 196
(2010/04/27)
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- S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES
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The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
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- CATHEPSIN CYSTEINE PROTEASE INHIBITORS
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The present invention relates to novel compounds of the formula (I), wherein R'-R7, X, Y, D and n are as defined in the specification. These compounds are cysteine protease inhibitors which include but are not limited to inhibitors of cathepsms K, L, S an
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Page/Page column 52
(2008/12/04)
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- ACETYLENIC SULFONAMIDE THIOL TACE INHIBITORS
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Compounds of formula (B): (1a), or (1b), (1c) are provided wherein the variables are as defined herein which are useful in disease conditions mediated by TNF- alpha , such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple
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- Total syntheses of lyngbyabellins A and B, potent cytotoxic lipopeptides from the marine cyanobacterium Lyngbya majuscula
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The first total syntheses of lyngbyabellins A and B, Lyngbya majuscula derived lipopeptides, are described. The functionalized thiazole carboxylic acid units were prepared by the oxidative dehydrogenation of the corresponding thiazolidines with chemical manganese dioxide. The asymmetric synthesis of the dichlorinated β-hydroxy acid by a chiral oxazaborolidinone mediated aldol reaction. Finally, fragment condensation followed by macrolactamization provided lyngbyabellin A. The total synthesis of lyngbyabellin B was accomplished by formation of the sensitive thiazoline ring after the macrolactamization.
- Yokokawa, Fumiaki,Sameshima, Hirofumi,Katagiri, Daichi,Aoyama, Toyohiko,Shioiri, Takayuki
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p. 9445 - 9458
(2007/10/03)
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- Total synthesis of lyngbyabellin A, a potent cytotoxic metabolite from the marine cyanobacterium Lyngbya majuscula
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The first total synthesis of lyngbyabellin A, a novel peptolide from the marine cyanobacterium Lyngbya majuscula, is described. Both functionalized thiazole carboxylic acid units were synthesized using our CMD (chemical manganese dioxide) oxidation from the corresponding thiazolidines. The asymmetric synthesis of the dichlorinated β-hydroxy acid was achieved by the chiral oxazaborolidinone mediated aldol reaction. Finally, fragment condensation followed by the macrolactamization provided lyngbyabellin A.
- Yokokawa, Fumiaki,Sameshima, Hirofumi,Shioiri, Takayuki
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p. 4171 - 4174
(2007/10/03)
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- Titanium(IV)-mediated tandem deprotection-cyclodehydration of protected cysteine N-amides: Biomimetic syntheses of thiazoline- and thiazole-containing heterocycles
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(matrix presented) The scope and limitations of TiCl4-mediated Δ2-thiazoline synthesis via tandem deprotection-dehydrocyclization of trityl-protected cysteine N-amides is presented. While chemical yields are acceptable (53-96%), the
- Raman, Prakash,Razavi, Hossein,Kelly, Jeffery W.
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p. 3289 - 3292
(2007/10/03)
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- Cyclic thioether peptide mimetics as VCAM-VLA-4 antagonists
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Selective substitution of a sulfur atom by carbon in a highly potent 13-membered cyclic disulfide was accomplished by intramolecular displacement of a bromide. The potency of the resulting thioethers in the VCAM/VLA-4 assay was dependant on ring size and the position of the sulfur atom. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Fotouhi, Nader,Joshi, Pramod,Tilley, Jefferson W.,Rowan, Karen,Schwinge, Virginia,Wolitzky, Barry
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p. 1167 - 1169
(2007/10/03)
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- Oxidative Deblocking of the 4-Methoxybenzyl Thioether Protecting Group: Application to the Directed Synthesis of Poly-cystinyl Peptides
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The 4-methoxybenzyl thioether protecting group is deblocked efficiently by oxidation with the homogeneous electron transfer agent tris(4-bromophenyl)ammoniumyl (2.+) leading to the disulfide in high yields.S-(4-methoxybenzyl)cysteine derivatives like 9 in this way can be transformed into the corresponding cystine derivatives like 10 in 90percent yield.Many N and carboxy protecting groups like the Boc and Z group and tert-butyl or benzyl ester functions are stable under the cleavage conditions.On the other hand the 4-methoxybenzyl thioether protecting group is totally unaffected by the conditions for oxidative deblocking of the S-trityl functions by either iodine or rhodanolysis.This opens up new opportunities for the directed synthesis of cystinyl peptides with more than one intra- or interchain disulfide bridge.Application of the new method to the synthesis of a cystine peptide with one intrachain S-S-bridge and a double-chain biscystinyl peptide is reported.
- Platen, Martin,Steckhan, Eberhard
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p. 1563 - 1576
(2007/10/02)
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