22537-07-1Relevant articles and documents
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.
IDH2 mutant inhibitor with macrocyclic structure, and medical applications thereof
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Paragraph 0110-0111; 0114, (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.
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
, 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.