23314-24-1Relevant articles and documents
Supramolecular cross-linked networks via host-guest complexation with cucurbit[8]uril
Appel, Eric A.,Biedermann, Frank,Rauwald, Urs,Jones, Samuel T.,Zayed, Jameel M.,Scherman, Oren A.
, p. 14251 - 14260 (2010)
The ability to finely tune the solution viscosity of an aqueous system is critical in many applications ranging from large-scale fluid-based industrial processes to free-standing hydrogels important in regenerative medicine, controlled drug delivery, and 'green' self-healing materials. Herein we demonstrate the use of the macrocyclic host molecule cucurbit[8]uril (CB[8]) to facilitate reversible cross-linking of multivalent copolymers with high binding constants (Ka > 1011-1012 M-2) leading to a supramolecular hydrogel. Multivalent copolymers were prepared by free radical polymerization techniques and contained either pendant methyl viologen (a good first guest for CB[8]) or naphthoxy derivatives (good second guests for CB[8]). A colorless solution of the two multivalent copolymers bearing first and second guests, respectively, can be transformed into a highly viscous, colored supramolecular hydrogel with the cross-link density being easily controlled through CB[8] addition. Moreover, the cross-links (1:1:1 supramolecular ternary complexes of CB[8]/viologen/naphthoxy) are dynamic and stimuli-responsive, and the material properties can be modulated by temperature or other external stimuli. Rheological characterization of the bulk material properties of these dynamically cross-linked networks provided insight into the kinetics of CB[8] ternary complexation responsible for elastically active cross-linking with a second guest dissociation rate constant (kd) of 1200 s-1 for the ternary complex. These materials exhibited intermediate mechanical properties at 5 wt % in water (plateau modulus = 350-600 Pa and zero-shear viscosity = 5-55 Pa?s), which is complementary to existing supramolecular hydrogels. Additionally, these supramolecular hydrogels exhibited thermal reversibility and subsequent facile modulation of microstructure upon further addition of CB[8] and thermal treatment. The fundamental knowledge gained from the study of these dynamic materials will facilitate progress in the field of smart, self-healing materials, self-assembled hydrogels, and controlled solution viscosity.
SELECTIVE NON-CYCLIC NUCLEOTIDE ACTIVATORS FOR THE CAMP SENSOR EPAC1
-
Paragraph 00168; 00169; 00198; 00246, (2021/09/26)
The invention relates generally to novel EPAC1 activators, such as Formula (I) and (II) and the preparation thereof as well as the use of EPAC1 activators disclosed herein as to selectively activate EPAC1 in cells.
Synthesis and Biochemical Evaluation of Noncyclic Nucleotide Exchange Proteins Directly Activated by cAMP 1 (EPAC1) Regulators
Wang, Pingyuan,Luchowska-Stańska, Urszula,Van Basten, Boy,Chen, Haiying,Liu, Zhiqing,Wiejak, Jolanta,Whelan, Padraic,Morgan, David,Lochhead, Emma,Barker, Graeme,Rehmann, Holger,Yarwood, Stephen J.,Zhou, Jia
, p. 5159 - 5184 (2020/06/03)
Exchange proteins directly activated by cAMP (EPAC) play a central role in various biological functions, and activation of the EPAC1 protein has shown potential benefits for the treatment of various human diseases. Herein, we report the synthesis and biochemical evaluation of a series of noncyclic nucleotide EPAC1 activators. Several potent EPAC1 binders were identified including 25g, 25q, 25n, 25u, 25e, and 25f, which promote EPAC1 guanine nucleotide exchange factor activity in vitro. These agonists can also activate EPAC1 protein in cells, where they exhibit excellent selectivity toward EPAC over protein kinase A and G protein-coupled receptors. Moreover, 25e, 25f, 25n, and 25u exhibited improved selectivity toward activation of EPAC1 over EPAC2 in cells. Of these, 25u was found to robustly inhibit IL-6-activated signal transducer and activator of transcription 3 (STAT3) and subsequent induction of the pro-inflammatory vascular cell adhesion molecule 1 (VCAM1) cell-adhesion protein. These novel EPAC1 activators may therefore act as useful pharmacological tools for elucidation of EPAC function and promising drug leads for the treatment of relevant human diseases.
AMINOETHYLATION PROCESS HAVING IMPROVED YIELD OF ARYLOXYALKYLENE AMINE COMPOUNDS AND REDUCED UREA BY-PRODUCTS
-
Paragraph 0060, (2014/03/25)
Disclosed is a process for preparing an aryloxyalkylene amine compound via an aminoethylation reaction comprising: a) reacting an aromatic hydroxyl compound in the presence of a basic catalyst with a 2-oxazolidinone compound of the formula II to form an intermediate reaction product; wherein R3 is selected from the group consisting of hydrogen or lower alkyl having 1 to 6 carbon atoms, R4 is selected from the group consisting of hydrogen, straight or branched chain alkyl having from one to six carbon atoms, phenyl, alkaryl, or arylalkyl; and b) reacting the intermediate product of step a) with a polyalkylene polyamine.
Biaryl-based anion receptors bearing thiourea groups: Fluoride anion receptor
Takahashi, Yohei,Endo, Masatoshi,Ito, Kazuaki
, p. 237 - 245 (2014/06/09)
The synthesis, characterization and binding studies with anions for biaryl-based anion receptors bearing thiourea groups have been described. The results revealed that receptors (1 and 2) showed good selectivity and binding affinity for F-, and among them binaphthyl-based receptor (1a) showed the best binding affinity for F-in comparison to other tested anions (Cl-, Br-, I-, NO-3 ; HSO-4 ; AcO-And H2PO-4 ). This is probably due to the fact that the moderate rigidity of binaphthyl skeleton in 1a is able to provide the better geometry of two thiourea groups for incorporating F-into the binding pocket. The higher basicity of F-Also participated in this selectivity. Springer Science+Business Media Dordrecht 2013.
IRREVERSIBLE COVALENT INHIBITORS OF THE GTPASE K-RAS G12C
-
Page/Page column 65; 66, (2014/09/29)
Irreversible inhibitors of K-Ras, H-Ras or N-ras protein comprising a G12C mutation are provided. Also disclosed are methods to regulate the activity of K-Ras, H-Ras or N-ras protein comprising G12C mutation and methods to disease mediated by K-Ras, H-Ras or N-ras G12C.
Novel TypeII Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents
Schrader, Florian C.,Glinca, Serghei,Sattler, Julia M.,Dahse, Hans-Martin,Afanador, Gustavo A.,Prigge, Sean T.,Lanzer, Michael,Mueller, Ann-Kristin,Klebe, Gerhard,Schlitzer, Martin
, p. 442 - 461 (2013/08/25)
Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood- and pre-erythrocytic liver stages of the parasite. P.falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial typeII fatty acid biosynthesis (FASII). It has been shown to be essential for liver-stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood-stage parasite growth with IC50 values of 1.7 and 3.0μM and lead to a more prominent developmental attenuation of liver-stage parasites than the gold-standard drug, primaquine.
Structure-affinity studies for a novel series of homochiral naphtho and tetrahydronaphtho analogues of α1 antagonist WB-4101
Bolchi, Cristiano,Catalano, Paolo,Fumagalli, Laura,Gobbi, Marco,Pallavicini, Marco,Pedretti, Alessandro,Villa, Luigi,Vistoli, Giulio,Valoti, Ermanno
, p. 4937 - 4951 (2007/10/03)
A number of enantiomeric pairs of naphthodioxane, tetrahydronaphthodioxane and naphthoxy analogues of WB-4101 (1) were designed and synthesized in order to improve the selectivity profile of the parent compound, hopefully in favour of the α1a-AR with respect to the other two α1 subtypes and the 5-HT1A receptor. The new compounds 2-8 and, in addition, the two enantiomers of 1 were tested in binding assays on the α1a-AR, α1b-AR, α1d-AR, and the 5-HT1A receptor. Two of them, namely the naphtho- and tetrahydronaphthodioxane derivatives (S)-2 and (S)-3, showed lower, but significantly more specific α1a affinity than (S)-1, while the two enantiomers of the 2-methoxy-1-naphthoxy analogue 6 maintained most of the very high α1a affinity of (S)-1 and its α1a versus α1b selectivity slightly increasing the α1a/α1d and α1a/5HT 1A affinity ratios. The SAR data were evaluated in the light of known α1 subtype pharmacophores and of the α1a-AR binding mode of WB-4101 resultant from literature mutagenesis studies disclosing some interesting consonances with these models.
Anti-inflammatory guanidines
-
, (2008/06/13)
A compound having the formula STR1 where Ar=naphthyl, biphenyl, or quinolinyl; X=oxygen or NH; Y=2 to 8; R1 =phenyl, substituted phenyl, hydrogen, lower alkyl; and R2 is the same or different from R3 and is alkyl, cycloalkyl, phenyl, substituted phenyl, thiazolyl; and the pharmaceutically acceptable salts thereof. Compounds of this general formula are useful as anti-inflammatories, and as anti-psoriatic agents.
