6608-47-5Relevant articles and documents
FGFR4 Inhibitor. Compositions and their use in pharmaceutical preparations
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Paragraph 0088-0091, (2021/10/27)
The invention provides 3 inhibitor which takes 4 - 4 dihydropyrimidine [5 - d,2] pyrimidine - (1H) FGFR4 ketone as a mother nucleus and has a covalent structure. The examples give 9 specific compounds and kinase inhibitory activity testing of these 9 compounds, wherein LX08 for FGFR4 kinase inhibitory activity is only 7 nm, lower than FIIN - 2 of the active control, and potential application prospects. In addition, by subjecting the synthesized compound to MALDI-TOF mass spectrometry, we found that compounds of LX01, LX05, LX06, LX07, LX08 are covalently bound to FGFR4 of Cys552, cannot covalently bind FGFR4 of Cys477, and LX09 are FGFR4 inhibitors which can be covalently bound to the two cysteines Cys552 and Cys477 in FGFR4.
Ring closing metathesis and metal-catalyzed cyclopropanation for the preparation of sultone derivatives
Ali, Korany A.,Metz, Peter
, p. 19 - 29 (2019/04/17)
Ring closing metathesis (RCM) using Grubbs catalyst 2nd generation as a catalyst was applied to prepare series of novel unsaturated sultones with high yields. Many attempts, were applied for the cyclopropanation of the allylic sultones by Simmon-smith cyclopropanation using diethyl zinc/diiodomethane or Zn-Cu/diiodomethane but in each case the corresponding cyclic adduct was not formed. A novel palladium or preferably rhodium-catalyzed cyclopropanation of unsaturated sultones with ethyl diazoacetate was achieved by the transition metal-catalyzed transfer of a CH-CO2Et unit. The reaction was applied by a portion-wise addition of ethyl diazoacetate over 6h to a mixture of the sultones and palladium(II) acetate or rhodium(II) acetate dimer under low temperature (0-20 o C). The desired products of the cyclopropanation were achieved in each case, as a single diastereomer with 33- 37% yield in the allylic sultones and 10% for vinylic sultone.
Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors
Rowlands, Rachel A.,Cato, M. Claire,Waldschmidt, Helen V.,Bouley, Renee A.,Chen, Qiuyan,Avramova, Larisa,Larsen, Scott D.,Tesmer, John J. G.,White, Andrew D.
supporting information, p. 1628 - 1634 (2019/12/03)
The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating heart failure and other diseases such as cancer. Although advances have been made toward developing inhibitors that are selective for GRK2, there have been far fewer reports of GRK5 selective compounds. Herein, we describe the development of GRK5 subfamily selective inhibitors, 5 and 16d that covalently interact with a nonconserved cysteine (Cys474) unique to this subfamily. Compounds 5 and 16d feature a highly amenable pyrrolopyrimidine scaffold that affords high nanomolar to low micromolar activity that can be easily modified with Michael acceptors with various reactivities and geometries. Our work thereby establishes a new pathway toward further development of subfamily selective GRK inhibitors and establishes Cys474 as a new and useful covalent handle in GRK5 drug discovery.
Synthesis, bioconjugation and stability studies of [18F]ethenesulfonyl fluoride
Zhang, Bo,Pascali, Giancarlo,Wyatt, Naomi,Matesic, Lidia,Klenner, Mitchell A.,Sia, Tiffany R.,Guastella, Adam J.,Massi, Massimiliano,Robinson, Andrea J.,Fraser, Benjamin H.
, p. 847 - 856 (2018/08/03)
Fluorine-18 labelled prosthetic groups (PGs) are often necessary for radiolabelling sensitive biological molecules such as peptides and proteins. Several shortcomings, however, often diminish the final yield of radiotracer. In an attempt to provide higher yielding and operationally efficient tools for radiolabelling biological molecules, we describe herein the first radiochemical synthesis of [18F]ethenesulfonyl fluoride ([18F]ESF) and its Michael conjugation with amino acids and proteins. The synthesis of [18F]ESF was optimised using a microfluidic reactor under both carrier-added (c.a.) and no-carrier-added (n.c.a.) conditions, affording, in a straightforward procedure, 30-50% radiochemical yield (RCY) for c.a. [18F]ESF and 60-70% RCY for n.c.a. [18F]ESF. The conjugation reactions were performed at room temperature using 10?mg/mL precursor in aqueous/organic solvent mixtures for 15?min. The radiochemical stability of the final conjugates was evaluated in injectable formulation and rat serum, and resulted strongly substrate dependent and generally poor in rat serum. Therefore, in this work we have optimised a straightforward synthesis of [18F]ESF and its Michael conjugation with model compounds, without requiring chromatographic purification. However, given the general low stability of the final products, further studies will be required for improving conjugate stability, before assessing the use of this PG for PET imaging.
A convenient synthesis of (E)-conjugated polyene sulfonyl derivatives with excellent stereospecificity
Yu, Chunyan,Lv, Zhongwen,Xu, Sheng,Zhang, Jun
supporting information, p. 3234 - 3237 (2018/07/25)
A highly selective synthesis of conjugated polyene sulfonyl derivatives is described via the elimination of disulfonyl chloride with readily accessible raw material dihaloalkane. The protocol offers a convenient way to form sulfonamides, sulfonates and even sulfones. Furthermore, this method was manipulated under mild condition with simple operation in high yield to afford only trans products.
MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Paragraph 00787, (2017/08/01)
Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
Vinyl sulfonic acid ester derivative, polymer compound and photoresist composition
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Paragraph 0094; 0095, (2018/10/16)
Provided is a photoresist composition which comprises a polymer that contains a specific vinylsulfonic acid ester derivative as constituent units and which exhibits improved LWR and can yield a high-resolution pattern. The specific vinylsulfonic acid ester derivative is represented by formula (1) [wherein R1 is a hydrogen atom or methyl; W is alkylene or a cyclic hydrocarbon group; n is 0 to 1; and A is a group represented by any of formulae (A-1) to (A-4) [wherein R2 to R11 are each independently a hydrogen atom, alkyl, a cyclic hydrocarbon group, or the like; R9 and R10 may together represent -CH2-, -CH2CH2-, -O-, or -S-; Y is an oxygen atom or >NR13 (wherein R13 is a hydrogen atom, alkyl or the like); and Z is >C=O or >SO2]].
Enantioselective template-directed [2+2] photocycloadditions of isoquinolones: Scope, mechanism and synthetic applications
Coote, Susannah C.,P?thig, Alexander,Bach, Thorsten
supporting information, p. 6906 - 6912 (2015/04/27)
A strategy for the enantioselective [2+2] photocycloaddition of isoquinolones with alkenes is presented, in which the formation of a supramolecular complex between a chiral template and the substrate ensures high enantioface differentiation by shielding one face of the substrate. Fifteen different electron-deficient alkenes and ten different substituted isoquinolones undergo efficient photocycloaddition, yielding the cyclobutane products in excellent yields and with outstanding regio-, diastereo- and enantioselectivities (up to 990 ee). The mechanism of the reaction is investigated by means of triplet sensitization/quenching and radical clock experiments, the results of which are consistent with the involvement of a triplet excited state and a 1,4-biradical intermediate. The variety of functionalized cyclobutanes obtained using this approach can be further increased by straightforward synthetic transformations of the photoadducts, allowing rapid access to libraries of compounds for various applications.
Stereocontrolled synthesis of a C1-C10 building block ("Southwestern Moiety") for the unnatural enantiomers of the polyene polyol antibiotics filipin III and pentamycin: A sultone-forming ring-closing metathesis for protection of hom
Walleser, Patrick,Brueckner, Reinhard
, p. 3210 - 3224 (2014/06/09)
In C2-symmetric diol 10 one OH group was substituted by crotonic acid and the other was incorporated in an ethenesulfonate. A twofold ring-closing metathesis under forcing conditions provided unsaturated lactone/unsaturated sultone 24. Conjugat
Stilbene vinyl sulfonamides as fluorogenic sensors of and traceless covalent kinetic stabilizers of transthyretin that prevent amyloidogenesis
Suh, Eul Hyun,Liu, Yu,Connelly, Stephen,Genereux, Joseph C.,Wilson, Ian A.,Kelly, Jeffery W.
supporting information, p. 17869 - 17880 (2014/01/06)
Small molecules that react selectively with a specific non-enzyme drug-target protein in a complex biological environment without displacement of a leaving group (tracelessly) are rare and highly desirable. Herein we describe the development of a family o
