22537-07-1Relevant academic research and scientific papers
Formation of Self-Templated 2,6-Bis(1,2,3-triazol-4-yl)pyridine [2]Catenanes by Triazolyl Hydrogen Bonding: Selective Anion Hosts for Phosphate
Byrne, Joseph P.,Blasco, Salvador,Aletti, Anna B.,Hessman, Gary,Gunnlaugsson, Thorfinnur
, p. 8938 - 8943 (2016)
We report the remarkable ability of 2,6-bis(1,2,3-triazol-4-yl)pyridine (btp) compounds 2 with appended olefin amide arms to self-template the formation of interlocked [2]catenane structures 3 in up to 50 % yield when subjected to olefin ring-closing metathesis in CH2Cl2. X-ray diffraction crystallography enabled the structural characterization of both the [2]catenane 3 a and the non-interlocked macrocycle 4 a. These [2]catenanes showed selective triazolyl hydrogen-bonding interactions with the tetrahedral phosphate anion when screened against a range of ions; 3 a,b are the first examples of selective [2]catenane hosts for phosphate.
Acetyl Coenzyme A Analogues as Rationally Designed Inhibitors of Citrate Synthase
Bello, Davide,Rubanu, Maria Grazia,Bandaranayaka, Nouchali,G?tze, Jan P.,Bühl, Michael,O'Hagan, David
, p. 1174 - 1182 (2019)
In this study, we probed the inhibition of pig heart citrate synthase (E.C. 4.1.3.7) by synthesising seven analogues either designed to mimic the proposed enolate intermediate in this enzyme reaction or developed from historical inhibitors. The most potent inhibitor was fluorovinyl thioether 9 (Ki=4.3 μm), in which a fluorine replaces the oxygen atom of the enolate. A comparison of the potency of 9 with that of its non-fluorinated vinyl thioether analogue 10 (Ki=68.3 μm) revealed a clear “fluorine effect” favouring 9 by an order of magnitude. The dethia analogues of 9 and 10 proved to be poor inhibitors. A methyl sulfoxide analogue was a moderate inhibitor (Ki=11.1 μm), thus suggesting hydrogen bonding interactions in the enolate site. Finally, E and Z propenoate thioether isomers were explored as conformationally constrained carboxylates, but these were not inhibitors. All compounds were prepared by the synthesis of the appropriate pantetheinyl diol and then assembly of the coenzyme A structure according to a three-enzyme biotransformation protocol. A quantum mechanical study, modelling both inhibitors 9 and 10 into the active site indicated short CF???H contacts of ≈2.0 ?, consistent with fluorine making two stabilising hydrogen bonds, and mimicking an enolate rather than an enol intermediate. Computation also indicated that binding of 9 to citrate synthase increases the basicity of a key aspartic acid carboxylate, which becomes protonated.
Enantioselective Synthesis of Pyrrolizidinone Scaffolds through Multiple-Relay Catalysis
Escolano, Marcos,Torres Fernández, Javier,Rabasa-Alca?iz, Fernando,Sánchez-Roselló, María,Del Pozo, Carlos
, p. 9433 - 9438 (2020)
A triple-tandem protocol for the synthesis of the pyrrolizidinone skeleton has been devised. It involves a cross metathesis-intramolecular aza-Michael reaction-intramolecular Michael addition tandem sequence, starting from N-pentenyl-4-oxo-2-alkenamides and conjugated ketones. In the presence of two cooperative catalysts, namely the second-generation Hoveyda-Grubbs catalyst and (R)-TRIP-derived BINOL phosphoric acid, this multiple-relay catalytic process takes place in good yields and outstanding levels of diastero- and enantioselectivity with the simultaneous generation of three contiguous stereocenters
Palladium(II)-Catalyzed Aminotrifluoromethoxylation of Alkenes: Mechanistic Insight into the Effect of N-Protecting Groups
Chen, Chaohuang,Chen, Pinhong,Hou, Chuanqi,Liu, Guosheng
supporting information, p. 346 - 350 (2020/05/25)
An efficient palladium-catalyzed regioselective 5-exo aminotrifluoromethoxylation of alkenes has been established herein, which provides a practical route towards the synthesis of OCF3-containing pyrrolidines. tert-Butyloxycarbonyl (Boc) as an amino protecting group plays a significant role in both the chemo- and regioselectivities. In addition, preliminary mechanistic studies reveal that the amino protecting group of substrates and the counter anion of palladium catalyst play critical roles in reaction efficiency presumably due to an isomerization of alkyl- Pd(II) intermediates. Moreover, the asymmetric 5-exo aminotrifluoromethoxylation reaction has also been achieved by introducing a sterically bulky pyridinyl-oxazoline ligand.
Cross-Module Enoylreduction in the Azalomycin F Polyketide Synthase
Zhai, Guifa,Wang, Wenyan,Xu, Wei,Sun, Guo,Hu, Chaoqun,Wu, Xiangming,Cong, Zisong,Deng, Liang,Shi, Yanrong,Leadlay, Peter F.,Song, Heng,Hong, Kui,Deng, Zixin,Sun, Yuhui
supporting information, p. 22738 - 22742 (2020/10/12)
The colinearity of canonical modular polyketide synthases, which creates a direct link between multienzyme structure and the chemical structure of the biosynthetic end-product, has become a cornerstone of knowledge-based genome mining. Herein, we report genetic and enzymatic evidence for the remarkable role of an enoylreductase in the polyketide synthase for azalomycin F biosynthesis. This internal enoylreductase domain, previously identified as acting only in the second of two chain extension cycles on an initial iterative module, is shown to also catalyze enoylreduction in trans within the next module. The mechanism for this rare deviation from colinearity appears to involve direct cross-modular interaction of the reductase with the longer acyl chain, rather than back transfer of the substrate into the iterative module, suggesting an additional and surprising plasticity in natural PKS assembly-line catalysis.
IDH2 mutant inhibitor with macrocyclic structure, and medical applications thereof
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, (2020/05/29)
The present invention discloses a macrocyclic compound with a structure represented by a general formula (I), and a medical use thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein L represents (CRaRb)n, 1-3 CRaRb groups can be replaced by O, NH, S or CH=CH, Z represents CRaRb, O, -NH-C(=O)-, -O-C(=O)- or -NH-, T is CH or N, X represents H, halogen, C3-C6 cycloalkyl, C1-C6 alkyl or C1-C6 haloalkyl, n is 4-10, and Ra and Rb are respectively and independently selected from H, halogen and C1-C6 alkyl. The inhibition effect of the macrocyclic compound provided by the invention on IDH2 is superior to the inhibition effect of the existing drug at a kinase level. According to the invention, the solubility of molecules and the overall fat solubility can be improved, so that the macrocyclic compound has the potential of penetrating through a blood-brain barrier, and is beneficial to solving the problem of brain tumors compared with the prior art.
A Peptide Backbone Stapling Strategy Enabled by the Multicomponent Incorporation of Amide N-Substituents
Ricardo, Manuel G.,Marrrero, Javiel F.,Valdés, Oscar,Rivera, Daniel G.,Wessjohann, Ludger A.
, p. 769 - 774 (2019/01/04)
The multicomponent backbone N-modification of peptides on solid-phase is presented as a powerful and general method to enable peptide stapling at the backbone instead of the side chains. This work shows that a variety of functionalized N-substituents suitable for backbone stapling can be readily introduced by means of on-resin Ugi multicomponent reactions conducted during solid-phase peptide synthesis. Diverse macrocyclization chemistries were implemented with such backbone N-substituents, including the ring-closing metathesis, lactamization, and thiol alkylation. The backbone N-modification method was also applied to the synthesis of α-helical peptides by linking N-substituents to the peptide N-terminus, thus featuring hydrogen-bond surrogate structures. Overall, the strategy proves useful for peptide backbone macrocyclization approaches that show promise in peptide drug discovery.
APOPTOSIS SIGNAL-REGULATING KINASE INHIBITORS AND USES THEREOF
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Paragraph 00232; 00228, (2019/04/09)
Described herein are ASK1 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of blood disease, autoimmune disorders, pulmonary disorders, hypertension, inflammatory diseases, fibrotic diseases, diabetes, diabetic nephropathy, renal diseases, respiratory diseases, cardiovascular diseases, acute lung injuries, acute or chronic liver diseases, and neurodegenerative diseases.
Dual Role of Vinyl Sulfonamides as N-Nucleophiles and Michael Acceptors in the Enantioselective Synthesis of Bicyclic δ-Sultams
Mulet, Cristina,Escolano, Marcos,Llopis, Sebastián,Sanz, Sergio,Ramírez de Arellano, Carmen,Sánchez-Roselló, María,Fustero, Santos,del Pozo, Carlos
supporting information, p. 2885 - 2893 (2018/08/17)
A new methodology for the synthesis of enantiomerically enriched bicyclic δ-sultams is described, involving an initial organocatalytic intramolecular aza-Michael reaction of vinyl sulfonamides bearing a conjugated ketone at a remote position. The resulting Michael adducts were then subjected to an intramolecular conjugate addition over the vinyl sulfone moiety, thus rendering the final bicyclic sultams containing two stereocenters. The key point of this strategy relies on the use of vinyl sulfonamides as both, nitrogen nucleophiles and Michael acceptors. The use of phosphazene-derived bases avoided the racemization of the intermediate derivatives, rendering 6-membered ring bicyclic δ-sultams in enantiomerically enriched manner with a small erosion of enantiopurity. Anyway, after recrystallization, final sultams were obtained in almost enantiomerically pure form. Nevertheless, the enantioselective synthesis of either 5-membered ring products or benzofused derivatives was found to be out of the scope of our strategy. (Figure presented.).
One-pot Construction of Difluorinated Pyrrolizidine and Indolizidine Scaffolds via Copper-Catalyzed Radical Cascade Annulation
Wang, Xiaoyang,Li, Miao,Yang, Yanyan,Guo, Minjie,Tang, Xiangyang,Wang, Guangwei
supporting information, p. 2151 - 2156 (2018/04/26)
A convenient approach to the synthesis of diverse difluorinated nitrogen-containing polycycles via a copper-catalyzed radical cascade annulation of amine-containing olefins and ethyl bromodifluoroacetate was developed. Three new bonds, including a Csp3 ?CF2 and two C?N bonds, are forged simultaneously in this strategy. Through this strategy, a series of difluorinated pyrrolizidine and indolizidine derivatives have been conveniently synthesized in good yields. (Figure presented.).
