7661-20-3Relevant academic research and scientific papers
Repurposing the 3-Isocyanobutanoic Acid Adenylation Enzyme SfaB for Versatile Amidation and Thioesterification
Zhu, Mengyi,Wang, Lijuan,He, Jing
supporting information, p. 2030 - 2035 (2020/11/30)
Genome mining of microbial natural products enables chemists not only to discover the bioactive molecules with novel skeletons, but also to identify the enzymes that catalyze diverse chemical reactions. Exploring the substrate promiscuity and catalytic mechanism of those biosynthetic enzymes facilitates the development of potential biocatalysts. SfaB is an acyl adenylate-forming enzyme that adenylates a unique building block, 3-isocyanobutanoic acid, in the biosynthetic pathway of the diisonitrile natural product SF2768 produced by Streptomyces thioluteus, and this AMP-ligase was demonstrated to accept a broad range of short-chain fatty acids (SCFAs). Herein, we repurpose SfaB to catalyze amidation or thioesterification between those SCFAs and various amine or thiol nucleophiles, thereby providing an alternative enzymatic approach to prepare the corresponding amides and thioesters in vitro.
A method of preparing intermediates [...]
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Paragraph 0022; 0033-0036, (2017/01/23)
A disclosed preparation method for an apixaban intermediate comprises the following steps: step (1), performing an amidation reaction shown in the specification on a compound 3 and a compound M in an organic solvent under the effect of an organic alkali to obtain a reaction solution containing a compound 3'; and step (2), under the effect of an inorganic base, directly performing an nucleophilic substitution reaction shown in the specification on the reaction solution obtained in the step (1) to prepare a compound 4, and performing a nitration reaction on the compound 4 under the effect of concentrated sulfuric acid and concentrated nitric acid to prepare a compound 5. The preparation method provided by the invention is low in cost, simple in operation and suitable for industrialization.
Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
Zhang, Xian,He, Yantao,Liu, Sijiu,Yu, Zhihong,Jiang, Zhong-Xing,Yang, Zhenyun,Dong, Yuanshu,Nabinger, Sarah C.,Wu, Li,Gunawan, Andrea M.,Wang, Lina,Chan, Rebecca J.,Zhang, Zhong-Yin
experimental part, p. 2482 - 2493 (2010/09/03)
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors.
Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents
Zhou, Bo,He, Yantao,Zhang, Xian,Xu, Jie,Luo, Yong,Wang, Yuehong,Franzblau, Scott G.,Yang, Zhenyun,Chan, Rebecca J.,Liu, Yan,Zheng, Jianyu,Zhang, Zhong-Yin
scheme or table, p. 4573 - 4578 (2010/10/03)
Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.
Derivatives of salicylic acid as inhibitors of YopH in yersinia pestis
Huang, Zunnan,He, Yantao,Zhang, Xian,Gunawan, Andrea,Wu, Li,Zhang, Zhong-Yin,Wong, Chung F.
scheme or table, p. 85 - 99 (2011/03/19)
Yersinia pestis causes diseases ranging from gastrointestinal syndromes to bubonic plague and could be misused as a biological weapon. As its protein tyrosine phosphatase YopH has already been demonstrated as a potential drug target, we have developed two series of forty salicylic acid derivatives and found sixteen to have micromolar inhibitory activity. We designed these ligands to have two chemical moieties connected by a flexible hydrocarbon linker to target two pockets in the active site of the protein to achieve binding affinity and selectivity. One moiety possessed the salicylic acid core intending to target the phosphotyrosine-binding pocket. The other moiety contained different chemical fragments meant to target a nearby secondary pocket. The two series of compounds differed by having hydrocarbon linkers with different lengths. Before experimental co-crystal structures are available, we have performed molecular docking to predict how these compounds might bind to the protein and to generate structural models for performing binding affinity calculation to aid future optimization of these series of compounds.
Rapid assembly and in situ screening of bidentate inhibitors of protein tyrosine phosphatases
Srinivasan, Rajavel,Uttamchandani, Mahesh,Yao, Shao Q.
, p. 713 - 716 (2007/10/03)
We have successfully designed and synthesized a small library of protein tyrosine phosphatase (PTP) inhibitors, in which the so-called "click chemistry" or Cu(I)-catalyzed 1,3-dipolar alkyne-azide coupling reaction was carried out for rapid assembly of 66 different bidentate compounds. Subsequent in situ enzymatic screening revealed a potential PTP1B inhibitor (IC50 = 4.7 μM) which is 10-100 fold more potent than other PTPs.
Novel inhibitors of human histone deacetylases: Design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates
Suzuki, Takayoshi,Nagano, Yuki,Kouketsu, Akiyasu,Matsuura, Azusa,Maruyama, Sakiko,Kurotaki, Mineko,Nakagawa, Hidehiko,Miyata, Naoki
, p. 1019 - 1032 (2007/10/03)
To find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) was designed and synthesized. In this series, compound 7, in which the hydroxamic acid of SAHA is replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. In cancer cell growth inhibition assay, S-isobutyryl derivative 51 showed strong activity, and its potency was comparable to that of SAHA. The cancer cell growth inhibitory activity was verified to be the result of histone hyperacetylation and subsequent induction of p21WAF1/CIP1 by Western blot analysis. Kinetical enzyme assay and molecular modeling suggest the thiol formed by enzymatic hydrolysis within the cell interacts with the zinc ion in the active site of HDACs.
The extraordinary reactions of phenyldimethylsilyllithium with N,N-disubstituted amides
Buswell, Marina,Fleming, Ian,Ghosh, Usha,Mack, Stephen,Russell, Matthew,Clark, Barry P.
, p. 3006 - 3017 (2007/10/03)
The reactions of the silyllithium reagent with tertiary amides was discussed. The enediamines were easily isomerized from cis to trans, easily oxidized to dienediamines and were hydrolyzed to α-aminoketones. If the two equivalents of the silyllithium reagent were used, the product was an α-silylamine. The results show that each member of the homologous series of amides gives rise to a substantially different product.
β-Cyclodextrin Host-Guest Complexes Probed under Thermodynamic Equilibrium: Thermodynamics and AFM Force Spectroscopy
Auletta, Tommaso,De Jong, Menno R.,Mulder, Alart,Van Veggel, Frank C. J. M.,Huskens, Jurriaan,Reinhoudt, David N.,Zou, Shan,Zapotoczny, Szczepan,Schoenherr, Holger,Vancso, G. Julius,Kuipers, Laurens
, p. 1577 - 1584 (2007/10/03)
The rupture forces of individual host-guest complexes between β-cyclodextrin (β-CD) heptathioether monolayers on Au(111) and several surface-confined guests were measured in aqueous medium by single molecule force spectroscopy using an atomic force microscope, Anilyl, toluidyl, tert-butylphenyl, and adamantylthiolss (0.2-1%) were immobilized in mixed monolayers with 2-mercaptoethanol on gold-coated AFM tips, For all guests and for all surface coverages, the force-displacement curves measured between the functionalized tips and monolayers of β-CD exhibited single, as well as multiple, pull-off events, The histograms of the pull-off forces showed several maxima at equidistant forces, with force quanta characteristic for each guest of 39 ± 15, 45 ± 15, 89 ± 15, and 102 ± 15 pN, respectively. These force quanta were independent of the loading rate, indicating that, because of the fast complexation/decomplexation kinetics, the rupture forces were probed under thermodynamic equilibrium. The force values followed the same trend as the free binding energy ΔG° measured for model guest compounds in solution or on β-CD monolayers, as determined by microcalorimetry and surface plasmon resonance measurements, respectively, A descriptive model was developed to correlate quantitatively the pull-off force values with the ΔG° of the complexes, based on the evaluation of the energy potential landscape of tip-surface interaction.
Thiol-based SAHA analogues as potent histone deacetylase inhibitors
Suzuki, Takayoshi,Kouketsu, Akiyasu,Matsuura, Azusa,Kohara, Arihiro,Ninomiya, Shin-Ichi,Kohda, Kohfuku,Miyata, Naoki
, p. 3313 - 3317 (2007/10/03)
In order to find novel nonhydroxamate histone deacetylase (HDAC) inhibitors, a series of thiol-based compounds modeled after suberoylanilide hydroxamic acid (SAHA) was synthesized, and their inhibitory effect on HDACs was evaluated. Compound 6, in which t
