3156-42-1Relevant articles and documents
Geometrically Selective Denitrative Trifluoromethylthiolation of β-Nitrostyrenes with AgSCF3for (E)-Vinyl Trifluoromethyl Thioethers
Fang, Ge,Hong, Jianquan,Huang, Shuai,Jiang, Chao,Liu, Yang,Zhang, Wei,Zheng, Changge
supporting information, (2020/07/03)
An efficient copper(II)-promoted denitrative trifluoromethylthiolation under mild reaction conditions has been developed for vinyl trifluoromethyl thioethers to construct Cvinyl-SCF3 bonds with stable AgSCF3 as a source of the trifluoromethylthio. This reaction system tolerates a broad range of functional groups to commendably achieve a high product yield and excellent stereoselectivity of E/Z.
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.
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.
Preparation method of nitroolefin derivative with nitrate as nitro source
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Paragraph 0042; 0049-0054; 0061-0063, (2019/08/20)
The invention relates to a nitroolefin derivative with nitrate as nitro source and a preparation method thereof. Under the atmosphere of nitrogen, an olefin compound, nitrate, trimethylchlorosilane (TMSC1) and copper salt are stirred in acetonitrile at 0-30 DEG C; in addition, the reaction degree is monitored by using a TLC point plate; after the olefin compound is completely consumed, alkali is added to an obtained mixture to be stirred for 20-30 min; then after a solvent is removed from an obtained mixture by using a rotary evaporator, the nitroolefin derivative can be obtained through silicagel column purification. Compared with the prior art, the nitroolefin derivative with the nitrate as the nitro source, provided by the invention, has the advantages of mild reaction condition, high yield, high E type selectivity and the like.
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.
Metal-free, room temperature, acid-K2S2O8 mediated method for the nitration of olefins: An easy approach for the synthesis of nitroolefins
Ambala, Srinivas,Singh, Rohit,Singh, Maninder,Cham, Pankaj Singh,Gupta, Ria,Munagala, Gurunadham,Yempalla, Kushalava Reddy,Vishwakarma, Ram A.,Singh, Parvinder Pal
, p. 30428 - 30431 (2019/10/04)
Here, we have developed a simple, room temperature method for the nitration of olefins by using inexpensive sodium nitrite as a source of nitro groups in the presence of trifluoroacetic acid (TFA) and potassium persulfate (K2S2O8) under an open atmosphere. Styrenes and mono-substituted olefins give stereo-selective corresponding E-nitroolefins under optimized conditions, however, 1,1-bisubstituted olefins give a mixture of E- and Z-nitroolefins. The optimized conditions work well with electron-donating, electron-withdrawing, un-substituted and heterocyclic styrenes and mono-substituted olefins and give corresponding nitroolefins with good to excellent yields.
Increasing C-Terminal Hydrophobicity Improves the Cell Permeability and Antiproliferative Activity of PACE4 Inhibitors against Prostate Cancer Cell Lines
Dianati, Vahid,Kwiatkowska, Anna,Couture, Frédéric,Desjardins, Roxane,Dory, Yves L.,Day, Robert
, p. 8457 - 8467 (2018/09/27)
The serine protease, PACE4, is a proprotein convertase that plays a substantial role in malignancy of prostate cancer. Our initial selective PACE4 inhibitor (Ac-LLLLRVKR-NH2) has evolved to the current lead compound C23 (Ac-dLeu-LLLRVK-Amba), w
Improving the Selectivity of PACE4 Inhibitors through Modifications of the P1 Residue
Dianati, Vahid,Navals, Pauline,Couture, Frédéric,Desjardins, Roxane,Dame, Anthony,Kwiatkowska, Anna,Day, Robert,Dory, Yves L.
, p. 11250 - 11260 (2019/01/04)
Paired basic amino acid cleaving enzyme 4 (PACE4), a serine endoprotease of the proprotein convertases family, has been recognized as a promising target for prostate cancer. We previously reported a selective and potent peptide-based inhibitor for PACE4, named the multi-Leu peptide (Ac-LLLLRVKR-NH2 sequence), which was then modified into a more potent and stable compound named C23 with the following structure: Ac-dLeu-LLLRVK-Amba (Amba: 4-amidinobenzylamide). Despite improvements in both in vitro and in vivo profiles of C23, its selectivity for PACE4 over furin was significantly reduced. We examined other Arg-mimetics instead of Amba to regain the lost selectivity. Our results indicated that the replacement of Amba with 5-(aminomethyl)picolinimidamide increased affinity for PACE4 and restored selectivity. Our results also provide a better insight on how structural differences between S1 pockets of PACE4 and furin could be employed in the rational design of selective inhibitors.
Direct dihalo-alkoxylation of nitroalkenes leading to β,β-dihalo-β-nitroethyl alkyl ethers
Hao, Feiyue,Yokoyama, Soichi,Nishiwaki, Nagatoshi
, p. 2768 - 2775 (2018/04/26)
A highly efficient one-pot synthesis of β,β-dihalo-β-nitroethyl alkyl ethers is achieved by the treatment of nitroalkenes with alcohols and N-halosuccinimides in the presence of sodium hydride. The notable advantages of this protocol are that it involves simple experimental manipulations and tolerates a wide range of functional groups. Further transformations of the obtained ethers, such as allylation and conversion to β,β-dihalogenated vinyl ethers, are also investigated.
