- Genetically encoded cleavable protein photo-cross-linker
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We have developed a genetically encoded, selenium-based cleavable photo-cross-linker that allows for the separation of bait and prey proteins after protein photo-cross-linking. We have further demonstrated the efficient capture of the in situ generated selenenic acid on the cleaved prey proteins. Our strategy involves tagging the selenenic acid with an alkyne-containing dimethoxyaniline molecule and subsequently labeling with an azide-bearing fluorophore or biotin probe. This cleavage-and-capture after protein photo-cross-linking strategy allows for the efficient capture of prey proteins that are readily accessible by two-dimensional gel-based proteomics and mass spectrometry analysis.
- Lin, Shixian,He, Dan,Long, Teng,Zhang, Shuai,Meng, Rong,Chen, Peng R.
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Read Online
- Discovery of Indole Derivatives as Novel and Potent Dengue Virus Inhibitors
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3-Acyl-indole derivative 1 was identified as a novel dengue virus (DENV) inhibitor from a DENV serotype 2 (DENV-2) phenotypic antiviral screen. Extensive SAR studies led to the discovery of new derivatives with improved DENV-2 potency as well as activity in nanomolar to micromolar range against the other DENV serotypes. In addition to the potency, physicochemical properties and metabolic stability in rat and human microsomes were improved during the optimization process. Chiral separation of the racemic mixtures showed a clear preference for one of the two enantiomers. Furthermore, rat pharmacokinetics of two compounds will be discussed in more detail, demonstrating the potential of this new series of pan-serotype-DENV inhibitors.
- Bardiot, Dorothée,Koukni, Mohamed,Smets, Wim,Carlens, Gunter,McNaughton, Michael,Kaptein, Suzanne,Dallmeier, Kai,Chaltin, Patrick,Neyts, Johan,Marchand, Arnaud
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p. 8390 - 8401
(2018/09/25)
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- N-PIPERIDIN-4-YL DERIVATIVES
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The invention relates to a N-piperidin-4-yl derivative having the general Formula I or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same and to the use of said N-piperidin-4-yl derivatives for the treatment and prevention of endometriosis, for the treatment and prevention of pre-menopausal and peri-menopausal hormone-dependent breast cancer, for contraception, or for the treatment of uterine fibroids or other menstrual-related disorders.
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Page/Page column 24-25
(2013/04/10)
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- 3-Aryl-4-methyl-2-quinolones Targeting Multiresistant Staphylococcus aureus Bacteria
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The NorA efflux pump lowers intracellular fluoroquinolone concentrations by expelling antibiotics through the membrane of Staphylococcus aureus. We identified 3-aryl-4-methyl-2-quinolin-2-ones as compounds able to restore the activity of the NorA substrate, ciprofloxacin, against resistant S.aureus strains, and acting as efflux pump inhibitors (EPI). In particular, 5-hydroxy-7-methoxy-4-methyl-3-phenylquinolin-2-one (6c) presents both an EPI and an antimicrobial effect. Its efficacy and safety make it a potential candidate for further investigations.
- Doleans-Jordheim, Anne,Veron, Jean-Baptiste,Fendrich, Olivier,Bergeron, Emmanuelle,Montagut-Romans, Adrien,Wong, Yung-Sing,Furdui, Bianca,Freney, Jean,Dumontet, Charles,Boumendjel, Ahcene
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p. 652 - 657
(2013/08/22)
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- Synthesis of substituted carbazoles, indoles, and dibenzofurans by vinylic to aryl palladium migration
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Substituted carbazoles, indoles, and dibenzofurans are readily prepared in moderate to excellent yields by the palladium-catalyzed cross-coupling of alkynes and appropriately substituted aryl iodides. This process proceeds by carbopalladation of the alkyn
- Zhao, Jian,Larock, Richard C.
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p. 5340 - 5348
(2007/10/03)
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- Identification of Novel Binding Interactions in the Development of Potent, Selective 2-Naphthamidine Inhibitors of Urokinase. Synthesis, Structural Analysis, and SAR of N-Phenyl Amide 6-Substitution
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The preparation and assessment of biological activity of 6-substituted 2-naphthamidine inhibitors of the serine protease urokinase plasminogen activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a starting point based on synthetic considerations and on modeling of substituent vectors. Phenyl amides at the 6-position were found to improve binding; replacement of the amide with other two-atom linkers proved ineffective. The phenyl group itself is situated near the S1′ subsite; substitutions off of the phenyl group accessed S1′ and other distant binding regions. Three new points of interaction were defined and explored through ring substitution. A solvent-exposed salt bridge with the Asp60A carboxylate was formed using a 4-alkylamino group, improving affinity to Ki = 40 nM. Inhibitors also accessed two hydrophobic regions. One interaction is characterized by a tight hydrophobic fit made with a small dimple largely defined by His57 and His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as Ki = 6 nM, and many compounds had Ki 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.
- Wendt, Michael D.,Rockway, Todd W.,Geyer, Andrew,McClellan, William,Weitzberg, Moshe,Zhao, Xumiao,Mantei, Robert,Nienaber, Vicki L.,Stewart, Kent,Klinghofer, Vered,Giranda, Vincent L.
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p. 303 - 324
(2007/10/03)
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- Therapeutic compounds
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Compounds of the formula (I) for use as an estrogen receptor-β-selective ligand are described wherein: X is O or S; and R1, R3 R6 are as described in the specification. The use of these compounds in treating Alzheimer's disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis and prostate cancer is described; as are processes for making them.
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