- Identification of a selective, activity-based probe for glyceraldehyde 3-phosphate dehydrogenases
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Exceptionally specific: The natural-product-like structural complexity of a bicyclic hydantoin was exploited to generate the novel, highly specific activity-based profiling probe (ABPP) Mrl-Rh (Rh=rhodamine; see picture) for glyceraldehyde 3-phosphate dehydrogenases. This probe can be used to investigate activity changes of this enzyme class during plant-pathogen interactions. Copyright
- Kaschani, Farnusch,Clerc, Jerome,Krahn, Daniel,Bier, David,Hong, Tram Ngoc,Ottmann, Christian,Niessen, Sherry,Colby, Tom,Van Der Hoorn, Renier A. L.,Kaiser, Markus
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- Multimerization of an apoptogenic TRAIL-mimicking peptide by using adamantane-based dendrons
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We have developed a straightforward strategy to multimerize an apoptogenic peptide that mimics the natural tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by using adamantane-based dendrons as multivalent scaffolds. The selective binding a
- Lamanna, Giuseppe,Smulski, Cristian R.,Chekkat, Neila,Estieu-Gionnet, Karine,Guichard, Gilles,Fournel, Sylvie,Bianco, Alberto
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- Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis
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Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.
- Shi, Ying,Duan, Yan-Hui,Ji, Yue-Yang,Wang, Zhi-Long,Wu, Yan-Ran,Gunosewoyo, Hendra,Xie, Xiao-Yu,Chen, Jian-Zhong,Yang, Fan,Li, Jing,Tang, Jie,Xie, Xin,Yu, Li-Fang
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- Azido-Desferrioxamine Siderophores as Functional Click-Chemistry Probes Generated in Culture upon Adding a Diazo-Transfer Reagent
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This work aimed to undertake the in situ conversion of the terminal amine groups of bacterial desferrioxamine (DFO) siderophores, including desferrioxamine B (DFOB), to azide groups to enable downstream click chemistry. Initial studies trialed a precursor-directed biosynthesis (PDB) approach. Supplementing Streptomyces pilosus culture with blunt-end azido/amine non-native substrates designed to replace 1,5-diaminopentane as the native diamine substrate in the terminal amine position of DFOB did not produce azido-DFOB. Addition of the diazo-transfer reagent imidazole-1-sulfonyl azide hydrogen sulfate to spent S. pilosus medium that had been cultured in the presence of 1,4-diaminobutane, as a viable native substrate to expand the suite of native DFO-type siderophores, successfully generated the cognate suite of azido-DFO analogues. CuI-mediated or strain-promoted CuI-free click chemistry reactions between this minimally processed mixture and the appropriate alkyne-bearing biotin reagents produced the cognate suite of 1,4-disubstituted triazole-linked DFO-biotin compounds as potential molecular probes, detected as FeIII-loaded species. The amine-to-azide transformation of amine-bearing natural products in complex mixtures by the direct addition of a diazo-transfer reagent to deliver functional click chemistry reagents adds to the toolbox for chemical proteomics, chemical biology, and drug discovery.
- Gotsbacher, Michael P.,Codd, Rachel
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- Highly Regioselective 5-endo-tet Cyclization of 3,4-Epoxy Amines into 3-Hydroxypyrrolidines Catalyzed by La(OTf)3
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Highly regioselective intramolecular aminolysis of 3,4-epoxy amines has been achieved. Key features of this reaction are (1) chemoselective activation of epoxides in the presence of unprotected aliphatic amines in the same molecules by a La(OTf)3 catalyst and (2) excellent regioselectivity for anti-Baldwin 5-endo-tet cyclization. This reaction affords 3-hydroxy-2-alkylpyrrolidines stereospecifically in high yields. DFT calculations revealed that the regioselectivity might be attributed to distortion energies of epoxy amine substrates. The use of this reaction was demonstrated by the first enantioselective synthesis of an antispasmodic agent prifinium bromide.
- Hoshino, Yoshihiko,Iwabuchi, Yoshiharu,Kuriyama, Yuse,Sasano, Yusuke,Uesugi, Shun-ichiro,Yamaichi, Aoto
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p. 1961 - 1965
(2021/01/04)
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- (4-HYDROXYPYRROLIDIN-2-YL)-HYDROXAMATE COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands.
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Paragraph 0710
(2019/05/15)
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- (4-HYDROXYPYRROLIDIN-2-YL)-HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to bifunctional compounds of formula (I), which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands of formula (III).
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Paragraph 0878; 0879
(2019/05/15)
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- TETRAHYDROPYRIDOPYRIMIDINES AND TETRAHYDROPYRIDOPYRIDINES AS INHIBITORS OF HBSAG (HBV SURFACE ANTIGEN) AND HBV DNA PRODUCTION FOR THE TREATMENT OF HEPATITIS B VIRUS INFECTIONS
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The present invention provides tetrahydropyridopyrimidines and tetrahydropyridopyridines having the general formula (I) wherein R1, R2, U, W, X, Y and Z are as described herein, as inhibitors of HBsAg (HBV surface antigen) and HBV DNA production for the treatment and prophylaxis of hepatitis B virus infections.
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Page/Page column 114; 115
(2016/11/21)
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- Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis B virus infection
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The invention provides novel compounds having the general formula: wherein R1, R2, R3, R4, R5 and R6 are as described herein, compositions including the compounds and methods of using the compounds.
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Paragraph 1818; 1819
(2015/08/04)
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- NOVEL DIHYDROQUINOLIZINONES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The invention provides novel compounds having the general formula (I) wherein R1, R2 R3, R4, R5 and R6 are as described herein, compositions including the compounds and methods of using the compounds in the treatment of the hepatitis B virus.
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Page/Page column 274
(2015/09/23)
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- Synthesis and in vitro antitumor activity of novel 2-alkyl-5- methoxycarbonyl-11-methyl-6H-pyrido[4,3-b]carbazol-2-ium and 2-alkylellipticin-2-ium chloride derivatives
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Twenty-one types of novel ellipticine derivatives and pyridocarbazoles (5-methoxycarbonyl-11-methyl-6H-pyrido[4,3-b]carbazoles) with a nitrosourea moiety, linked by an oxydiethylene unit at the 2 position, were synthesized, and their cytotoxicity against HeLa S-3 cells was evaluated. Some of these new compounds exhibited potent antitumor activity by comparison with that of ellipticine.
- Mori, Ryota,Kato, Asako,Komenoi, Kousuke,Kurasaki, Haruaki,Iijima, Touru,Kawagoshi, Masashi,Kiran,Takeda, Sho,Sakai, Norio,Konakahara, Takeo
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- Chemical tagging of a drug target using 5-sulfonyl tetrazole
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Irreversible modification is one of the most promising strategies to identify cellular receptors of bioactive small molecules. Here we report that receptor proteins can be chemically tagged using a 5-sulfonyl tetrazole probe. 5-Sulfonyl tetrazole easily a
- Otsuki, Satsuki,Nishimura, Shinichi,Takabatake, Hisae,Nakajima, Kozue,Takasu, Yasuaki,Yagura, Toru,Sakai, Yuki,Hattori, Akira,Kakeya, Hideaki
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p. 1608 - 1611
(2013/04/10)
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- Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase
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Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological di
- Sadovski, Oleg,Hicks, Justin W.,Parkes, Jun,Raymond, Roger,Nobrega, José,Houle, Sylvain,Cipriano, Mariateresa,Fowler, Christopher J.,Vasdev, Neil,Wilson, Alan A.
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p. 4351 - 4357
(2013/07/27)
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- N -acetylgalactosamino dendrons as clearing agents to enhance liver targeting of model antibody-fusion protein
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Dendrimer clearing agents represent a unique class of compounds for use in multistep targeting (MST) in radioimmunotherapy and imaging. These compounds were developed to facilitate the removal of excess tumor-targeting monoclonal antibody (mAb) prior to a
- Yoo, Barney,Cheal, Sarah M.,Torchon, Geralda,Dilhas, Anna,Yang, Guangbin,Pu, Jun,Punzalan, Blesida,Larson, Steven M.,Ouerfelli, Ouathek
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p. 2088 - 2103
(2014/01/06)
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- Substituted cyclic compounds and mixtures comprising same
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Novel chemical compounds and mixtures of same are provided having antibacterial and other utilities. The mixtures preferably are formed by reacting a cyclic scaffold moiety with a set of chemical substituients. Libraries formed in accordance with the inve
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- Synthesis of polyazacyclophane-intercalator conjugates for combinatorial chemistry and RNA interaction studies
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Anthraquinone and pyrene intercalators were conjugated to different positions of several polyazapyridinocyclophanes by various linkers to provide thirteen new polyazacyclophane-intercalator conjugates 1-13. These resulting conjugates contain two or three constrained secondary nitrogen atoms on the ring, which may serve as nucleophilic, coordinating or hydrogen-bonding sites for combinatorial, RNA interaction and coordination studies.
- Wang,An,Haly,Cook
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p. 687 - 696
(2007/10/03)
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- Substituted amine derivatives, their production and use
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Substituted amino derivatives represented by the formula: STR1 wherein R1 and R2 each stand for an acyclic hydrocarbon residue or an alicyclic hydrocarbon residue; R3 and R4 each stand for hydrogen or a hydrocarbon residue optionally containing hetero-atom(s); A stands for a carbon chain having two or more carbon atoms optionally containing ether linkage or sulfide linkage, which may be substituted and which may per se form a ring; X1 and X2 each stand for oxygen atom or sulfur atom; and Y stands for amino group or an organic residue bonded through nitrogen atom, which may form a ring by combining with a carbon atom constituting A; and their salts have anti-arrhythmic activity and are useful for prevention and treatment of a variety of arrhythmias.
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