- Cobalt-Catalyzed Deoxygenative Hydroboration of Nitro Compounds and Applications to One-Pot Synthesis of Aldimines and Amides
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The commercially available and bench-stable Co(acac)2 ligated with bis[(2-diphenylphosphino)phenyl] ether (dpephos) was employed for selective room temperature hydroboration of nitro compounds with HBPin (TOF up to 4615 h?1), tolerating halide, hydroxy, amino, ether, ester, lactone, amide and heteroaromatic functionalities. These reactions offered a direct access to a variety of N-borylamines RN(H)BPin, which were in situ treated with aldehydes and carboxylic acids to produce a series of aldimines and secondary carboxamides without the need for dehydrating and/or coupling reagents. Combination of these transformations in a sequential one-pot manner allowed for direct and selective synthesis of aldimines and secondary carboxamides from readily available and inexpensive nitro compounds.
- Gudun, Kristina A.,Hayrapetyan, Davit,Khalimon, Andrey Y.,Segizbayev, Medet,Slamova, Ainur,Zakarina, Raikhan
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- Discovery of indole-3-butyric acid derivatives as potent histone deacetylase inhibitors
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In discovery of HDAC inhibitors (HDACIs) with improved anticancer potency, structural modification was performed on the previous derived indole-3-butyric acid derivative. Among all the synthesised compounds, molecule I13 exhibited high HDAC inhibitory and antiproliferative potencies in the in?vitro investigations. The IC50 values of I13 against HDAC1, HDAC3, and HDAC6 were 13.9, 12.1, and 7.71 nM, respectively. In the cancer cell based screening, molecule I13 showed increased antiproliferative activities in the inhibition of U937, U266, HepG2, A2780, and PNAC-1 cells compared with SAHA. In the HepG2 xenograft model, 50 mg/kg/d of I13 could inhibit tumour growth in athymic mice compared with 100 mg/kg/d of SAHA. Induction of apoptosis was revealed to play an important role in the anticancer potency of molecule I13. Collectively, a HDACI (I13) with high anticancer activity was discovered which can be utilised as a lead compound for further HDACI design.
- Chen, Yiming,Zhang, Lihui,Zhang, Lin,Jiang, Qixiao,Zhang, Lei
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p. 425 - 436
(2021/02/03)
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- Discovery of N-(2-Amino-4-Fluorophenyl)-4-[bis-(2-Chloroethyl)-Amino]-Benzamide as a Potent HDAC3 Inhibitor
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In discovery of HDAC inhibitors with improved activity and selectivity, fluorine substitution was performed on our previously derived lead compound. The synthesized molecules N-(2-amino-4-fluorophenyl)-4-[bis-(2-chloroethyl)-amino]-benzamide (FNA) exhibited class I (HDAC1, 2, and 3) selectivity in the in vitro enzymatic assay and especially potent against HDAC3 activity (IC50: 95.48 nM). The results of in vitro antiproliferative assay indicated that FNA exhibited solid tumor cell inhibitory activities with IC50 value of 1.30 μM against HepG2 cells compared with SAHA (17.25 μM). Moreover, the in vivo xenograft model study revealed that FNA could inhibit tumor growth with tumor growth inhibition (TGI) of 48.89% compared with SAHA (TGI of 48.13%). Further HepG2 cell–based apoptosis and cell cycle studies showed that promotion of apoptosis and G2/M phase arrest make contributions to the antitumor activity of FNA. In addition, drug combination results showed that 0.5 μM of FNA could improve the anticancer activity of taxol and camptothecin. The present studies revealed the potential of FNA utilized as a high potent lead compound for further discovery of isoform selective HDAC inhibitors.
- Chen, Yiming,Feng, Jinhong,Hu, Yajie,Song, Weiguo,Wang, Xuejian,Zhang, Lei
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- HDAC INHIBITORS AND USES THEREOF
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The present invention relates to histone deacetylase inhibitors, and to pharmaceutical compositions comprising the compounds, useful for the treatment of ischemia-reperfusion injury and for cardioprotection.
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- Discovery of N-(2-aminophenyl)-4-(bis(2-chloroethyl)amino)benzamide as a potent histone deacetylase inhibitor
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Inhibition of histone deacetylases (HDACs) has been an important emerging therapy for the treatment of multiple cancers. However, the application of HDAC inhibitors is restricted by the limited potency against solid tumors. In order to discover novel HDAC inhibitors with potent antitumor activities, nitrogen mustard group was introduced to the structure of CI994. The derived molecule N-(2-aminophenyl)-4-(bis(2-chloroethyl)amino) benzamide (NA) exhibited enzyme inhibitory pattern of class I selectivity with IC50 values of 95.2, 260.7, and 255.7 nM against HDAC1, HDAC2, and HDAC3, respectively. In the antiproliferative assay, NA exhibited 10.3-fold (2.66 μM) and 11.3-fold (1.73 μM) higher potency than did suberoylanilide hydroxamic acid (SAHA) (27.3 and 19.5 μM) in inhibition of A2780 and HepG2 cell growth, respectively. Further HepG2 cell-based cell cycle and apoptosis studies revealed that induction of the G2/M phase arrest and cell apoptosis contributes to the antitumor effects of NA. It is suggested that NA could be utilized as a lead compound in the development of bifunctional HDAC inhibitors for the treatment of solid tumors.
- Zhang, Lihui,Li, Xiaoyang,Chen, Yiming,Wan, Minghui,Jiang, Qixiao,Zhang, Li,James Chou,Song, Weiguo,Zhang, Lei
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- Aryl nitrogen mustard type histone deacetylation enzyme inhibitor as well as preparation method thereof and application thereof
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The invention discloses a powerful histone deacetylation enzyme inhibitor, relates to a compound with a structure as shown in formula I, various optical isomers thereof, a medically acceptable salt and a solvent compound. The invention further relates to a pharmaceutical composition comprising the compound with the structure as shown in formula I and the pharmaceutical purpose thereof. The powerful histone deacetylation enzyme inhibitor can effectively treat a disease with histone deacetylation enzyme activity abnormal expression. The formula is shown in the description.
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Paragraph 0069; 0070-0071; 0083-0084; 0096-0097
(2018/09/11)
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- Fluorescent-labeled amino acid as well as preparation method and application thereof
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The invention discloses a fluorescent-labeled amino acid. The fluorescent-labeled amino acid has the structure shown in a formula I: (the formula is shown in the description); stable covalent bondingis formed between an amino acid molecule and a fluorescence dye molecule; the fluorescent-labeled amino acid has high stability and high biocompatibility in the detection environments such as serum, and is suitable for detection of biological molecules such as protein and polypeptide inside and outside cells. Because the strokes shift of the fluorescence dye molecule is large, the fluorescent-labeled amino acid has the advantages of high fluorescence stability, high fluorescence quantum yield and high imaging result signal-to-noise ratio. The invention discloses a preparation method of the fluorescent-labeled amino acid. The preparation method is mild in reaction condition, simple to operate and high in reaction selectivity; the high-yield fluorescent-labeled amino acid can be prepared.
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Paragraph 0071; 0075; 0080-0083; 0110; 0114; 0120; 0121
(2018/12/13)
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- Histone deacetylase inhibitor N-(2'-aminophenyl)-4-(bis(2-chloroethyl)amino)benzamide, preparation method and application thereof
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Belonging to the technical field of medicinal chemistry, the invention in particular relates to a histone deacetylase inhibitor, a preparation method and application thereof. The invention provides a potent histone deacetylase inhibitor, the invention relates to a compound with a structural formula (I), and also relates to cis-trans isomers thereof, pharmaceutically acceptable salts, solvates and prodrugs. The invention also relates to a pharmaceutical composition containing the compound shown as structural formula (I) and pharmaceutical use thereof. The histone deacetylase inhibitor provided by the invention can effectively treat histone deacetylase activity abnormally expressed diseases.
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Paragraph 0044; 0045; 0046; 0047; 0048
(2017/08/28)
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- Development of N-hydroxybenzamide derivatives with indole-containing cap group as histone deacetylases inhibitors
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Histone deacetylases inhibitors (HDACIs) have captured more and more attention in many diseases therapies, of which cancer is the most intractable. A novel series of N-hydroxybenzamide derivatives containing indole cap group was designed and synthesized. Most compounds exhibited excellent HDACs inhibitory activity, especially 8q-8v with low nanomolar IC50 values (1.5-13.0 nM), which were much more potent than the positive control SAHA. The most potent compound 8r showed slightly higher growth inhibitory activity than SAHA in multiple tumor cell lines, even though, antiproliferative activity of 8r seemed inferior to its HDAC inhibition activity. Poor transcellular permeability obtained from the result of HDAC class I cellular assay could explain the inferior antiproliferative activity. In addition, 8r displayed similar HDAC IIa cellular activity to class I, which indicated 8r might be a potent pan-HDAC inhibitor.
- Li, Xiaoyang,Wu, Jingde,Li, Xiaoguang,Mu, Weiwei,Liu, Xueliang,Jin, Yiming,Xu, Wenfang,Zhang, Yingjie
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p. 6258 - 6270
(2015/09/28)
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- Histone deacetylase inhibitors with enhanced enzymatic inhibition effects and potent in vitro and in vivo antitumor activities
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In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for classa I HDACs over HDAC6, as demonstrated by enzyme selectivity assays. In vitro antiproliferation assay results show that representative compounds can selectively inhibit the growth of non-solid lymphoma and leukemic cells such as U937, K562, and HL60. In the in vivo antitumor assay, (S)-4-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2- phenylacetamido)-N-hydroxybenzamide (D17) showed better performance than SAHA in blocking U937 tumor growth. Western blot analysis revealed that representative molecules can block the function of both class I HDACs and HDAC6. More importantly, our western blot results reveal that the levels of some oncogenic proteins (p-Akt in the PI3K/AKT/mTOR signal pathway, c-Raf and p-Erk in the MAPK signal pathway) were dramatically down-regulated by our compounds in the U937 cell line rather than MDA-MB-231 cells. This distinction in cellular mechanism might be an important reason why the U937 cell line was found to more sensitive to our HDAC inhibitors than the MDA-MB-231 cell line.
- Zhang, Lei,Zhang, Yingjie,Chou, C. James,Inks, Elizabeth S.,Wang, Xuejian,Li, Xiaoguang,Hou, Jinning,Xu, Wenfang
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p. 638 - 648
(2014/03/21)
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- Discovery of a series of small molecules as potent histone deacetylase inhibitors
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A series of small molecules were designed and synthesized based on our previous virtual screening approach, which was performed to discover potent histone deacetylase inhibitors (HDACIs) with novel structures. The derived compounds were tested by Hela cell nucleus extract for enzyme inhibition assay. Tumor cell growth inhibition assays were performed using a series of tumor cell lines. Molecule 4h has the best performance among these compounds with enzyme inhibition IC50 of 0.14 μM and tumor cell growth inhibition IC50 of 1.85 (U937), 2.02 (HL60), 2.67 (K562). Docking studies showed that multiple H-bonds and hydrophobic interactions make 4h binding to the active site of HDAC. 4h has the advantage of low molecular weight, so a variety of structural modifications can be performed in our further studies.
- Zhang, Lei,Wang, Xuejian,Li, Xiaoguang,Xu, Wenfang
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p. 333 - 337
(2014/06/09)
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- A facile and efficient method for the selective deacylation of N-arylacetamides and 2-chloro-Narylacetamides catalyzed by SOCl2
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Thionyl chloride efficiently and selectively promoted the deacylation of N-arylacetamides and 2-chloro-N-arylacetamides, under anhydrous conditions, without effecting the ester group, aminosulfonyl group, or benzyloxyamide group. This method, which has been successfully applied to a variety of substrates including different N-arylacetamides and 2-chloro-N-arylacetamides, has the attractive advantages of inexpensive reagents, satisfactory selectivity, excellent yields, short reaction time, and convenient workup. This new method can probably be used to selectively deacylate between aromatic amides and alkyl amides. Springer Science+Business Media B.V. 2011.
- Wang, Gong-Bao,Wang, Lin-Fa,Li, Chao-Zhang,Sun, Jing,Zhou, Guang-Ming,Yang, Da-Cheng
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- Alternative method for the reduction of aromatic nitro to amine using TMDS-iron catalyst system
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The system 1,1,3,3-tetramethyldisiloxane (TMDS)/Fe(acac)3 is reported here as a new method to obtain amines from aromatic nitro compounds. Amines are synthetized in a straightforward step and are isolated as hydrochloride salts with good to excellent yields. This system has shown a good selectivity toward aryl-chloride, aryl-bromide, ester, carboxylic acid, and cyano groups. The reduction of alkylnitro compounds was unfortunately not possible using this method, only a mixture of mono and dialkylated amine was obtained.
- Pehlivan, Leyla,Métay, Estelle,Laval, Stéphane,Dayoub, Wissam,Demonchaux, Patrice,Mignani, Gérard,Lemaire, Marc
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experimental part
p. 1971 - 1976
(2011/04/22)
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- Reduction of aromatic and aliphatic esters using the reducing systems MoO2(acac)2 or V(O)(OiPr)3 in combination with 1,1,3,3-tetramethyldisiloxane
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An efficient reduction of aromatic and aliphatic esters with 1,1,3,3-tetramethyldisiloxane in combination with [MoO2(acac) 2] or [V(O)(OiPr)3] is reported. In the former system, the presence of triphenylphosphane oxide allows high conversion and good isolated yield to be reached. For the latter system, no ligand is necessary to obtain the corresponding alcohols with similar results. 1,1,3,3-Tetramethyldisiloxane in association with [MoO2(acac)2] or [V(O)(OiPr)3] was found to efficiently reduce aliphatic and aromatic esters. Copyright
- Pehlivan, Leyla,Metay, Estelle,Laval, Stephane,Dayoub, Wissam,Delbrayelle, Dominique,Mignani, Gerard,Lemaire, Marc
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experimental part
p. 7400 - 7406
(2012/01/06)
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- Iron-catalyzed selective reduction of nitro compounds to amines
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An efficient reduction of the nitro group with a catalytic amount of Fe(acac)3 and TMDS in THF at 60 °C affording the corresponding amine is described.
- Pehlivan, Leyla,Métay, Estelle,Laval, Stéphane,Dayoub, Wissam,Demonchaux, Patrice,Mignani, Gérard,Lemaire, Marc
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experimental part
p. 1939 - 1941
(2010/06/14)
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- Highly chemo- and regioselective reduction of aromatic nitro compounds using the system silane/oxo-rhenium complexes
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(Chemical Equation Presented) The reduction of aromatic nitro compounds to the corresponding amines with silanes catalyzed by high valent oxo-rhenium complexes is reported. The catalytic systems PhMe2SiH/ReIO 2(PPh3)2 (5 mol %) and PhMe2SiH/ ReOCl3(PPh3)2 (5 mol %) reduced efficiently a series of aromatic nitro compounds in the presence of a wide range of functional groups such as ester, halo, amide, sulfone, lactone, and benzyl. This methodology also allowed the regioselective reduction of dinitrobenzenes to the corresponding nitroanilines and the reduction of an aromatic nitro group in presence of an aliphatic nitro group. 2009 American Chemical Society.
- De Noronha, Rita G.,Romao, Carlos C.,Fernandes, Ana C.
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supporting information; experimental part
p. 6960 - 6964
(2010/03/03)
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- A convenient synthesis of amino acid methyl esters
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A series of amino acid methyl ester hydrochlorides were prepared in good to excellent yields by the room temperature reaction of amino acids with methanol in the presence of trimethylchlorosilane. This method is not only compatible with natural amino acids, but also with other aromatic and aliphatic amino acids.
- Li, Jiabo,Sha, Yaowu
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p. 1111 - 1119
(2008/09/21)
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- Organosilicon synthesis of isocyanates: III. Synthesis of aliphatic, carbocyclic, aromatic, and alkylaromatic isocyanatocatboxylic acid esters
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A series of aminoacid esters was prepared by treating the aminoacid suspensions in ethanol with thionyl chloride. Best conversion of aminoacid esters to corresponding isocyanates was achieved in the case of aromatic and carbocyclic aminoesters by phosgeneation of their N-silyl derivatives, and in the case of aliphatic and alkylaromatic aminoesters by phosgeneation of O-silyl or N,O-bissilylurethanes on their basis. In the last case additional step of esterification of the by-products isocyanatoalkylcarboxylic acid chlorides is required after phosgeneation. Unusual generation of cynnamates and intramolecular N→O-migration of trimethylsilyl group in the solutions of silylated alkylaromatic β-aminoacid esters were found. Pleiades Publishing, Inc., 2006.
- Lebedev,Lebedeva,Sheludyakov,Ovcharuk,Kovaleva,Ustinova
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p. 1069 - 1080
(2008/02/05)
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- PHOSPHONATE AND PHOSPHONAMIDE ENDOPEPTIDASE INHIBITORS
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Compounds of the formula STR1 wherein Y is O or NH and X is STR2 will inhibit the action of neutral endopeptidase. As a result, such compounds produce diuresis, natriuresis, and lower blood pressure as well as being useful in the treatment of congestive heart failure, relieving pain, and diarrhea when administered to a mammalian host.
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- Aminobenzoic and aminocyclohexanecarboylic acid compounds, compositions, and their method of use
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Compounds of the formula inhibit the action of neutral endopeptidase. As a result, such compounds produce diuresis, natriuresis, and lower blood pressure as well as being useful in the treatment of congestive heart failure, relieving pain, and diarrhea when administered to a mammalian host.
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