1979-49-3Relevant academic research and scientific papers
Rationalizing the Unprecedented Stereochemistry of an Enzymatic Nitrile Synthesis through a Combined Computational and Experimental Approach
Yavuzer, Hilmi,Asano, Yasuhisa,Gr?ger, Harald
supporting information, p. 19162 - 19168 (2021/07/26)
In this contribution, the unique and unprecedented stereochemical phenomenon of an aldoxime dehydratase-catalyzed enantioselective dehydration of racemic E- and Z-aldoximes with selective formation of both enantiomeric forms of a chiral nitrile is rationalized by means of molecular modelling, comprising in silico mutations and docking studies. This theoretical investigation gave detailed insight into why with the same enzyme the use of racemic E- and Z-aldoximes leads to opposite forms of the chiral nitrile. The calculated mutants with a larger or smaller cavity in the active site were then prepared and used in biotransformations, showing the theoretically predicted decrease and increase of the enantioselectivities in these nitrile syntheses. This validated model also enabled the rational design of mutants with a smaller cavity, which gave superior enantioselectivities compared to the known wild-type enzyme, with excellent E-values of up to E>200 when the mutant OxdRE-Leu145Phe was utilized.
Catalytic Asymmetric Construction of Tertiary Carbon Centers Featuring an α-Difluoromethyl Group with CF2H-CH2-NH2as the "building Block"
Gao, Fengyun,Guo, Yifei,Sun, Mengmeng,Wang, Yalan,Yang, Changyan,Wang, Yuqiang,Wang, Kairong,Yan, Wenjin
supporting information, p. 2584 - 2589 (2021/04/13)
We report here for the first time a novel difluoromethylated ketimine building block condensed by thioisatin and difluoroethylamine, offering efficient access to a broad range of enantioenriched products bearing difluoroethylamine units (27 examples, ≤98% yield, >99% ee) in the presence of quinine-derived squaramide. Further transformation of the intermediate would generate a variety of versatile functional blocks like α-difluoromethyl amines, β-amino acid, and β-diamine with retention of the enantiomeric excess at the difluoromethyl-bound carbon.
Organocatalytic Asymmetric Synthesis of Aza-Spirooxindoles via Michael/Friedel-Crafts Cascade Reaction of 1,3-Nitroenynes and 3-Pyrrolyloxindoles
Ni, Qijian,Wang, Xuyang,Zeng, Da,Wu, Qianling,Song, Xiaoxiao
supporting information, p. 2273 - 2278 (2021/04/05)
An asymmetric [3+3] cyclization of nitroenynes and 3-pyrrolyloxindoles has been realized with a chiral bifunctional squaramide catalyst. This Michael/Friedel-Crafts cascade strategy provides a facile and efficient access to enantioenriched polycyclic aza-spirooxindoles with 32-95% isolated yields and excellent stereocontrol under mild reaction conditions.
Biological evaluation and SAR analysis of novel covalent inhibitors against fructose-1,6-bisphosphatase
Chen, Haifeng,Guo, Yanrong,Han, Xinya,Hu, Wei,Huang, Yunyuan,Ren, Yanliang,Tang, Zilong,Wang, Qi,Wei, Lin,Xia, Qinfei,Yan, Jufen
supporting information, (2020/07/23)
Fructose-1,6-bisphosphatase (FBPase) is an attractive target for affecting the GNG pathway. In our previous study, the C128 site of FBPase has been identified as a new allosteric site, where several nitrovinyl compounds can bind to inhibit FBPase activity. Herein, a series of nitrostyrene derivatives were further synthesized, and their inhibitory activities against FBPase were investigated in vitro. Most of the prepared nitrostyrene compounds exhibit potent FBPase inhibition (IC50 3, CF3, OH, COOH, or 2-nitrovinyl were installed at the R2 (meta-) position of the benzene ring, the FBPase inhibitory activities of the resulting compounds increased 4.5–55 folds compared to those compounds with the same groups at the R1 (para-) position. In addition, the preferred substituents at the R3 position were Cl or Br, thus compound HS36 exhibited the most potent inhibitory activity (IC50 = 0.15 μM). The molecular docking and site-directed mutation suggest that C128 and N125 are essential for the binding of HS36 and FBPase, which is consistent with the C128-N125-S123 allosteric inhibition mechanism. The reaction enthalpy calculations show that the order of the reactions of compounds with thiol groups at the R3 position is Cl > H > CH3. CoMSIA analysis is consistent with our proposed binding mode. The effect of compounds HS12 and HS36 on glucose production in primary mouse hepatocytes were further evaluated, showing that the inhibition was 71% and 41% at 100 μM, respectively.
NCC Pincer Ni (II) Complexes Catalyzed Hydrophosphination of Nitroalkenes with Diphenylphosphine
Yan, Jing,Wang, Yan-Bing,Hou, Senyao,Shi, Linlin,Zhu, Xinju,Hao, Xin-Qi,Song, Mao-Ping
, (2020/08/21)
An efficient NCC pincer Ni (II)-catalyzed hydrophosphination of nitroalkenes with diphenylphosphine has been developed. Under the optimized conditions, both (hetero)aromatic and aliphatic nitroalkenes were well tolerated, irrespective of electronic effect, to provide the corresponding products in up to 99% yield.
Application of Fluorine- And Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators
Garai, Sumanta,Kulkarni, Pushkar M.,Schaffer, Peter C.,Leo, Luciana M.,Brandt, Asher L.,Zagzoog, Ayat,Black, Tallan,Lin, Xiaoyan,Hurst, Dow P.,Janero, David R.,Abood, Mary E.,Zimmowitch, Anaelle,Straiker, Alex,Pertwee, Roger G.,Kelly, Melanie,Szczesniak, Anna-Maria,Denovan-Wright, Eileen M.,Mackie, Ken,Hohmann, Andrea G.,Reggio, Patricia H.,Laprairie, Robert B.,Thakur, Ganesh A.
, p. 542 - 568 (2020/02/04)
Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, β-arrestin 2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both analogs also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while being devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.
Preparation method of beta-trans-nitroolefin
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Paragraph 0066-0068, (2020/06/17)
The invention relates to a preparation method of beta-trans-nitroolefin. The method comprises: sequentially adding an olefin compound, a nitration reagent and a solvent into a reaction container, mixing the substances uniformly, and carrying out constant temperature reaction for 18h under an illumination condition to obtain a reaction solution; and sequentially carrying out drying, concentration and column chromatography treatment on the reaction solution to obtain the beta-trans-nitroolefin compound. The method is simple and practicable, low in cost and high in product yield, can realize large-scale production, and has good industrial application prospects in the aspects of functional organic material, bioactive compound and drug synthesis.
Discovery of novel allosteric site and covalent inhibitors of FBPase with potent hypoglycemic effects
Huang, Yunyuan,Wei, Lin,Han, Xinya,Chen, Haifeng,Ren, Yanliang,Xu, Yanhong,Song, Rongrong,Rao, Li,Su, Chen,Peng, Chao,Feng, Lingling,Wan, Jian
supporting information, (2019/10/08)
Fructose-1,6-bisphosphatase (FBPase) is an essential enzyme of GNG pathway. Significant advances demonstrate the FBPase plays a critical role in treatment of diabetes. Numerous FBPase inhibitors were developed by targeting AMP site, nevertheless, none of these inhibitors has exhibited suitable potency and druggability. Herein, a new allosteric site (C128) on FBPase was discovered, and several nitrostyrene compounds exhibiting potent FBPase inhibitions were found covalently bind to C128 site on FBPase. Mutagenesis suggest that C128 is the only cysteine that can influence FBPase inhibition, the N125–S124–S123 pathway was most likely involved in allosteric signaling transmission between C128 and active site. However, these nitrostyrenes may bind with multiple cysteine besides C128 in FBPase. To improve pocket selectivity, a series of novel compounds (14a-14n) were re-designed rationally by integrating fragment-based covalent virtual screening and machine-learning-based synthetic complexity evaluation. As expected, the mass spectrometry validated that the proportion of title compounds binding to the C128 in FBPase was significantly higher than that of nitrostyrenes. Notably, under physiological and pathological conditions, the treatment of compounds 14b, 14c, 14i or 14n led to potent inhibition of glucose production, as well as decreased triglyceride and total cholesterol levels in mouse primary hepatocytes. We highlight a novel paradigm that molecular targeting C128 site on FBPase can have potent hypoglycemic effect.
Catalytic and Mechanistic Developments of the Nickel(II) Pincer Complex-Catalyzed Hydroarsination Reaction
Tay, Wee Shan,Lu, Yunpeng,Yang, Xiang-Yuan,Li, Yongxin,Pullarkat, Sumod A.,Leung, Pak-Hing
supporting information, p. 11308 - 11317 (2019/08/07)
Synthetic challenges have significantly slowed the development of the catalytic asymmetric hydroarsination reaction despite it being a highly attractive C?As bond formation methodology. In addition, there is a poor understanding of the main reaction steps in such reactions which limit further development in the field. Herein, key intermediates of the hydroarsination reaction catalyzed by a PCP NiII-Cl pincer complex are presented upon investigating the reaction with DFT calculations, conductivity measurements, NMR spectroscopy, and catalytic screening. The novel Ni–Cl–As interaction proposed was then contrasted against known NiII-catalyzed hydrophosphination reactions to highlight dissimilarities between them even though P and As share a close group relationship. Lastly, the asymmetric hydroarsination of nitroolefins was further developed to furnish a library of chiral organoarsines in up to 99 % yield and 80 % ee under mild conditions (?20 °C to RT) between 5 to 210 mins.
Synthetic Diversity from a Versatile and Radical Nitrating Reagent
Zhang, Kun,Jelier, Benson,Passera, Alessandro,Jeschke, Gunnar,Katayev, Dmitry
supporting information, p. 12929 - 12939 (2019/09/17)
We leverage the slow liberation of nitrogen dioxide from a newly discovered, inexpensive succinimide-derived reagent to allow for the C?H diversification of alkenes and alkynes. Beyond furnishing a library of aryl β-nitroalkenes, this reagent provides unparalleled access to β-nitrohydrins and β-nitroethers. Detailed mechanistic studies strongly suggest that a mesolytic N?N bond fragmentation liberates a nitryl radical. Using in situ photo-sensitized, electron paramagnetic resonance spectroscopy, we observed direct evidence of a nitryl radical in solution by nitrone spin-trapping. To further exhibit versatility of N-nitrosuccinimide under photoredox conditions, the late-stage diversification of an extensive number of C?H partners to prepare isoxazolines and isoxazoles is presented. This approach allows for the formation of an in situ nitrile oxide from a ketone partner, the presence of which is detected by the formation of the corresponding furoxan when conducted in the absence of a dipolarophile. This 1,3-dipolar cycloaddition with nitrile oxides and alkenes or alkynes proceeds in a single-operational step using a mild, regioselective, and general protocol with broad chemoselectivity.
