- Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif
-
Specialized cellular networks of oxidoreductases coordinate the dithiol/disulfide-exchange reactions that control metabolism, protein regulation, and redox homeostasis. For probes to be selective for redox enzymes and effector proteins (nM to μM concentrations), they must also be able to resist non-specific triggering by the ca. 50 mM background of non-catalytic cellular monothiols. However, no such selective reduction-sensing systems have yet been established. Here, we used rational structural design to independently vary thermodynamic and kinetic aspects of disulfide stability, creating a series of unusual disulfide reduction trigger units designed for stability to monothiols. We integrated the motifs into modular series of fluorogenic probes that release and activate an arbitrary chemical cargo upon reduction, and compared their performance to that of the literature-known disulfides. The probes were comprehensively screened for biological stability and selectivity against a range of redox effector proteins and enzymes. This design process delivered the first disulfide probes with excellent stability to monothiols yet high selectivity for the key redox-Active protein effector, thioredoxin. We anticipate that further applications of these novel disulfide triggers will deliver unique probes targeting cellular thioredoxins. We also anticipate that further tuning following this design paradigm will enable redox probes for other important dithiol-manifold redox proteins, that will be useful in revealing the hitherto hidden dynamics of endogenous cellular redox systems.
- Becker, Katja,Busker, Sander,Felber, Jan G.,Maier, Martin S.,Poczka, Lena,Scholzen, Karoline,Theisen, Ulrike,Thorn-Seshold, Julia,Thorn-Seshold, Oliver,Zeisel, Lukas,Arnér, Elias S. J.,Brandst?dter, Christina
-
supporting information
p. 8791 - 8803
(2021/06/27)
-
- Discovery of substituted 3H-pyrido[2,3-d]pyrimidin-4-ones as potent, biased, and orally bioavailable sst2 agonist
-
The discovery of a novel 3H-pyrido[2,3-d]pyrimidin-4-one series as potent and biased sst2 agonists is described. This class of molecules exhibits excellent sst2 potency and selectivity against sst1, sst3, and sst5 receptors, and they are significantly more potent at inhibiting cAMP production than inducing internalization. The orally bioavailable 6-(3-chloro-5-methylphenyl)-3-(3-fluoro-5-hydroxyphenyl)-5-({methyl[(2S)-pyrrolidin-2-ylmethyl]amino}methyl)-3H,4H-pyrido[2,3-d]pyrimidin-4-one (36) also suppresses GH secretion in GHRH-challenged rats in a dose-dependent manner.
- Betz, Stephen F.,Chen, Zhiyong,Kusnetzow, Ana Karin,Nguyen, Julie,Rico-Bautista, Elizabeth,Struthers, R. Scott,Tan, Hannah,Zhao, Jian,Zhu, Yunfei
-
supporting information
(2020/08/26)
-
- Compound and preparation method and application thereof
-
The invention discloses a compound as well as a preparation method and application thereof, and the structural formula of the compound is as shown in formula 1. The research finds that the compound provided by the invention can be applied to preparation o
- -
-
Paragraph 0073-0074; 0077
(2020/08/22)
-
- A One-Pot Iodo-Cyclization/Transition Metal-Catalyzed Cross-Coupling Sequence: Synthesis of Substituted Oxazolidin-2-ones from N-Boc-allylamines
-
A one-pot iodo-cyclization/transition metal-catalyzed cross-coupling sequence is reported to access various C5-functionalized oxazolidin-2-ones from unsaturated N-Boc-allylamines. Depending on the Grignard reagents used for the cross-coupling, e.g., aryl- or cyclopropylmagnesium bromide, a cobalt or copper catalyst has to be used to obtain the functionalized oxazolidin-2-ones in good yields.
- Chaumont-Olive, Pauline,Cossy, Janine
-
supporting information
(2020/05/14)
-
- Donor–Acceptor Complex Enables Alkoxyl Radical Generation for Metal-Free C(sp3)–C(sp3) Cleavage and Allylation/Alkenylation
-
The alkoxyl radical is an essential and prevalent reactive intermediate for chemical and biological studies. Here we report the first donor–acceptor complex-enabled alkoxyl radical generation under metal-free reaction conditions induced by visible light. Hantzsch ester forms the key donor–acceptor complex with N-alkoxyl derivatives, which is elucidated by a series of spectrometry and mechanistic experiments. Selective C(sp3)-C(sp3) bond cleavage and allylation/alkenylation is demonstrated for the first time using this photocatalyst-free approach with linear primary, secondary, and tertiary alkoxyl radicals.
- Zhang, Jing,Li, Yang,Xu, Ruoyu,Chen, Yiyun
-
supporting information
p. 12619 - 12623
(2017/09/11)
-
- SUBSTITUTED AMINO TRIAZOLES USEFUL AS HUMAN CHITINASE INHIBITORS
-
Disclosed are amino triazole compounds substituted with a piperidinyl ring that is itself substituted with a heterocyclic ring. These compounds are inhibitors of acidic mammalian chitinase and chitotriosidase. Also disclosed are methods of using the compounds to treat asthma reactions caused by allergens, as well as acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer.
- -
-
Page/Page column 86; 147; 148
(2017/03/21)
-
- Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
-
The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.
- -
-
Paragraph 0207; 0363-0365
(2016/10/20)
-
- NOVEL INDOLE DERIVATIVES AND THEIR USE IN NEURODEGENERATIVE DISEASES
-
The present invention relates to indole compounds, and pharmaceutically acceptable compositions thereof, useful as antagonists of P2X7, and for the treatment of P2X7-related disorders.
- -
-
Paragraph 0905-0906
(2016/11/24)
-
- PROCESS FOR MAKING TRICYCLIC LACTAM COMPOUNDS
-
Processes are described for the preparation of tricyclic lactam compound of Formula (I), having the structure and intermediates useful for the preparation of (I).
- -
-
Page/Page column 14
(2016/05/19)
-
- An expedient synthesis of oxazepino and oxazocino quinazolines
-
A synthetic route to a new class of privileged tri- and tetra-cyclic quinazolines containing a medium-sized ring is reported. An expedient synthetic route involving nucleophilic aromatic substitution, and sequential Niementowski and BOP-mediated ring clos
- Hensbergen, Albertus Wijnand,Mills, Vanessa R.,Collins, Ian,Jones, Alan M.
-
supporting information
p. 6478 - 6483
(2015/11/16)
-
- ARYL LACTAM KINASE INHIBITORS
-
The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.
- -
-
Page/Page column 181-182
(2015/11/02)
-
- Aryl vinyllactam serinekinase inhibitor
-
The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.
- -
-
Paragraph 0329
(2016/10/09)
-
- COMPOUNDS AND METHODS
-
Disclosed are compounds having the Formula (I), wherein X, Y, Z, R1, R2 and R3 are as defined herein, and methods of making and using the same.
- -
-
Page/Page column 144
(2011/12/14)
-
- Discovery of novel leukotriene A4 hydrolase inhibitors based on piperidine and piperazine scaffolds
-
Novel piperidine and piperazine derivatives have been designed and tested as inhibitors of LTA4 hydrolase (LTA4H). Most potent compounds showed good potency in both enzymatic and functional human whole blood assay. Crystallography studies further confirmed observed structure-activity relationship and LTA4H binding mode for analogs from the piperidine series.
- Sandanayaka, Vincent,Mamat, Bjorn,Bhagat, Nikhil,Bedell, Louis,Halldorsdottir, Gudrun,Sigthorsdottir, Heida,Andrésson, Thorkell,Kiselyov, Alex,Gurney, Mark,Singh, Jasbir
-
scheme or table
p. 2851 - 2854
(2010/08/06)
-
- Synthesis of 6- and 7-membered cyclic enaminones: Scope and mechanism
-
Six- and seven-membered cyclic enaminones can be prepared using common, environmentally benign reagents. Amino acids are used as synthetic precursors allowing diversification and the incorporation of chirality. The key reaction in this multistep process involves deprotection of Boc-amino ynones and subsequent treatment with methanolic K2CO3 to induce cyclization. A β-amino elimination side reaction was identified in a few labile substrates that led to either loss of stereochemical purity or degradation. This process can be mitigated in specific cases using mild deprotection conditions. NMR and deuterium-labeling experiments provided valuable insight into the workings and limitations of this reaction. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond-making and bond-breaking, thus changing the mode of addition to a 6-endo-trig cyclization. This method can be used to construct an array of monocyclic and bicyclic scaffolds, many of which are found in well-known natural products (e.g., indolizidine, quinolizidine, and Stemona alkaloids).
- Niphakis, Micah J.,Turunen, Brandon J.,Georg, Gunda I.
-
supporting information; scheme or table
p. 6793 - 6805
(2010/12/20)
-
- Synthesis of a model compound of corydendramine a via a julia coupling
-
The synthesis of the tetraenylpiperidine 12, which has the same core structure as the natural product corydendramine A, has been completed in eight steps starting from 2-piperidinemethanol 3 and trans,trans-2,6-nonadienal 6. The key step of the synthesis was a Julia coupling of sulfone (10) with aldehyde (5) to form a conjugated triene.
- McCrea-Hendrick, Maddy,Nichols, Christopher J.
-
experimental part
p. 3611 - 3620
(2009/12/09)
-
- Efficient synthesis of heterocyclic compounds using ethenetricarboxylic acid diesters
-
Ethenetricarboxylic acid diester 1a is a useful compound bearing two reactive sites, a CO2H group and a Michael acceptor. Reactions of 1a and reagents with oxygen and nitrogen nucleophilic moieties have been examined. The reaction of 1a with 2-
- Yamazaki, Shoko,Iwata, Yuko,Fukushima, Yugo
-
supporting information; experimental part
p. 655 - 659
(2009/06/20)
-
- FUSED THIOPHENE DERIVATIVES AS KINASE INHIBITORS
-
A series of 5,6-dihydro-1-benzothiophen-7(4H)-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
- -
-
Page/Page column 57
(2008/06/13)
-
- ACYCLIC 1,4-DIAMINES AND USES THEREOF
-
This invention relates to novel compounds useful in the treatment of diseases associated with TRPV4 channel receptor. More specifically, this invention relates to certain acyclic diamines, which are agonists of TRPV4 channel receptors.
- -
-
Page/Page column 49; 144-145
(2008/06/13)
-
- AZOLE-BASED PHOSPHODIESTERASE INHIBITORS
-
The present invention relates to phosphodiesterase (PDE) type IV selective inhibitors. Processes for the preparation of disclosed compounds of Formula (I), pharmaceutical compositions containing the compounds described herein and their use as PDE type IV selective inhibitors are provided.
- -
-
Page/Page column 59
(2010/11/24)
-
- Novel gamma-lactams as beta-secretase inhibitors
-
There is provided a series of novel substituted gamma-lactams of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R5 and R6 as defined herein, their ph
- -
-
Page/Page column 23
(2010/10/20)
-
- Investigations concerning the organolanthanide and group 3 metallocene-catalyzed cyclization-functionalization of nitrogen-containing dienes
-
Organolanthanide catalyzed cyclization-silylation of nitrogen-containing polyunsaturated systems allows access to core structures commonly found in naturally occurring alkaloids. Nitrogen-containing dienes with various substitution patterns were investigated. The method was most successful for substrates with terminal alkenes. Cyclization upon pendant 1,1-disubstituted olefins was not realized under various conditions. Interestingly, sterically hindered sulfonamides, which were previously believed to render the catalyst inactive, were actually compatible with the catalyst, thus affording the cyclized products after prolonged reaction times. Variations using fused ring systems were also investigated.
- Molander, Gary A.,Romero, Jan Antoinette C.
-
p. 2631 - 2643
(2007/10/03)
-
- POLYHETEROCYCLIC COMPOUNDS AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS
-
The present invention relates to new compounds of formula (I), wherein P, Q, X1, X2, X3, X4, X5, X6, R1, R2, R3, m, n, and p are as defined as in formula (I), or salts, or hydrates thereof, processes for their preparation and new intermediates used in the preparation thereof, pharmaceutical compositions containing said compounds and to the use of said compounds in therapy.
- -
-
Page/Page column 40
(2010/02/13)
-
- Design and synthesis of conformationally constrained 3-(N-alkylamino) propylphosphonic acids as potent agonists of sphingosine-1-phosphate (S1P) receptors
-
A series of conformationally constrained analogs of 3 were synthesized and evaluated as S1P receptor agonists. Several novel scaffolds were identified as suitable for further investigation. A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.
- Yan, Lin,Hale, Jeffrey J.,Lynch, Christopher L.,Budhu, Richard,Gentry, Amy,Mills, Sander G.,Hajdu, Richard,Keohane, Carol Ann,Rosenbach, Mark J.,Milligan, James A.,Shei, Gan-Ju,Chrebet, Gary,Bergstrom, James,Card, Deborah,Rosen, Hugh,Mandala, Suzanne M.
-
p. 4861 - 4866
(2007/10/03)
-
- Chemokine receptor binding heterocyclic compounds with enhanced efficacy
-
The invention relates to heterocyclic compounds consisting of a core nitrogen atom surrounded by three pendant groups, wherein two of the three pendant groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third pendant group contains N and optionally contains additional rings. The compounds bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
- -
-
Page/Page column 12-13
(2010/02/03)
-
- Pyrrolidinic and piperidinic ring fission by conjugate elimination
-
Treating N-substituted pyrrolidines and piperidines bearing an allylic chain α to the nitrogen with strong bases leads to the opening of the heterocycle and provides 1,3-dienes disubstituted with an alkoxy and an aminoalkyl chain. The effects of the base and the solvent have been studied, as well as the influence of the ring size and the nitrogen substituent. The results obtained suggest a possible pre-chelation of the base cation before the deprotonation.
- Acquadro, Francesco,Oulyadi, Hassan,Venturello, Paolo,Maddaluno, Jacques
-
p. 8759 - 8763
(2007/10/03)
-
- A new entry to 9-azabicyclo[3.3.1]nonanes using radical translocation/cyclisation reactions of 2-(but-3-ynyl)-1-(o-iodobenzoyl)piperidines
-
The 2-[4-(trimethylsilyl) but-3-ynyl]piperidines 16a-c, upon treatment with tributyltin hydride in the presence of azoisobutyronitrile in refluxing toluene, gave the 9-azabicyclo[3.3.1]nonanes 17a-c in high yields, respectively. Compound 17c was subjected to desilylation, ozonolysis, and subsequent 1,2-transposition of the resulting carbonyl group to give 9-benzoyl-1-methyl-9-azabicyclo[3.3.1]nonan-3-one, a potential precursor for the synthesis of (±)-euphococcinine.
- Sato, Tatsunori,Yamazaki, Taro,Nakanishi, Yumi,Uenishi, Jun-ichi,Ikeda, Masazumi
-
p. 1438 - 1443
(2007/10/03)
-
- CCR3 antagonists: a potential new therapy for the treatment of asthma. Discovery and structure-activity relationships.
-
CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.
- Wacker, Dean A,Santella 3rd., Joseph B,Gardner, Daniel S,Varnes, Jeffrey G,Estrella, Melissa,DeLucca, George V,Ko, Soo S,Tanabe, Keiichi,Watson, Paul S,Welch, Patricia K,Covington, Maryanne,Stowell, Nicole C,Wadman, Eric A,Davies, Paul,Solomon, Kimberly A,Newton, Robert C,Trainor, George L,Friedman, Steven M,Decicco, Carl P,Duncia, John V
-
p. 1785 - 1789
(2007/10/03)
-
- Quinone-cyclized porfiromycins
-
Mitomycin C and porfiromycin cyclization has been implicated in the pathway for KW-2149 and BMS-181174 function. The importance of the porfiromycin C(7) structure and nucleophile for quinone cyclization was determined showing that both C(7) and C(8) annul
- Na, Younghwa,Kohn, Harold
-
p. 1347 - 1363
(2007/10/03)
-
- New entry to alicyclic amines via alkylative fragmentation of cyclic aminoaldehyde tosylhydrazones
-
Tosylhydrazones of cyclic aminoaldehydes when exposed to aromatic and aliphatic Grignard reagents produce ring-opened acyclic unsaturated primary carbamates and carbamate alcohols in good yields. (C) 2000 Elsevier Science Ltd.
- Chandrasekhar,Reddy,Rajaiah
-
p. 10131 - 10134
(2007/10/03)
-
- Total synthesis of (+)-aloperine. Use of a nitrogen-bound silicon tether in an intramolecular diels-alder reaction
-
Enantioselective total syntheses of aloperine (1), N-methylaloperine (2), and N-allylaloperine (3) are reported. The central element of the synthetic strategy is an intramolecular Diels-Alder reaction in which the cycloaddends are tethered by a N-silylamine linkage. The total synthesis of 1 proceeds from commercially available 3-hydroxypiperidine hydrochloride (54) and (R)-pipecolinic acid (35) by way of nine isolated and purified intermediates. The synthesis is sufficiently efficient that gram quantities of (+)-aloperine (1) can be readily prepared. Early exploratory studies also introduced a convenient method for tethering cycloaddition partners with a sulfonamide unit to realize the intramolecular Diels-Alder cycloaddition of a vinylsulfonamide: 45 → 46.
- Brosius, Arthur D.,Overman, Larry E.,Schwink, Lothar
-
p. 700 - 709
(2007/10/03)
-
- Intramolecular aziridination: Decomposition of diazoamides with tethered imino bonds
-
(Matrix presented) Of three possible mechanistic pathways, tethered oximino ethers react intramolecularly with diazoamides to produce a diazabicyclo[5.1.0]-hexane aziridine containing skeleton. Several acyclic and cyclic templates were synthesized and reacted with rhodium catalysts to prepare their corresponding annulated aziridines. Anomalous behavior was discovered with the piperidine template, resulting in an aziridination occurring during the attempted diazo-transfer reaction, rather than the catalyzed carbenoid reaction.
- Wright, Dennis L.,McMills, Mark C.
-
p. 667 - 670
(2008/02/14)
-
- Short syntheses of (S)-pipecolic acid, (R)-coniine, and (S)-δ-coniceine using biocatalytically-generated chiral building blocks
-
The kinetic resolutions of both (±)-N-(benzyloxycarbonyl-2- (hydroxymethyl)piperidine [(±)-5] and (±)-N(tert-butoxycarbonyl)-2- (hydroxymethyl)piperidine [(±)-6] catalyzed by the enzyme acylase I from Aspergillus species (AA-I) afforded the chiral building blocks (S)-5 and (S)- 6, respectively; which were used for the syntheses of the title natural products and derivatives of (S)-pipecolic acid. The syntheses were short (2- 4 steps) and proceeded with satisfactory overall yield.
- Sanchez-Sancho, Francisco,Herradon, Bernardo
-
p. 1951 - 1965
(2007/10/03)
-
- Tartronic acids, their acetalic ethers and O-esters
-
Tartronic acid acetalic ethers and esters of the general formula: STR1 are provided and are useful in treatment of bone dysmetabolism. As examples, Ra and Rb may be hydrogen, B is a C2 -C12 acyl group, R is phenyl and n is 0-12.
- -
-
-
- A metallocarbenoid approach to the formation of spirocyclic ammonium ylides leading to the preparation of medium-sized azacane rings
-
A novel approach to azacyclooctene and azacyclononene containing substrates has been achieved via the intermediacy of a spirocyclic ammonium ylide derived from the diazodecomposition of a tethered α-diazoester moiety.
- Wright, Dennis L.,Weekly, R. Matt,Groff, Royce,McMills, Mark C.
-
p. 2165 - 2168
(2007/10/03)
-