- Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer
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NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed. With this goal in mind, based on NUAK inhibitor WZ4003, a series of derivatives has been synthesized and evaluated for anticancer activity. Compound 9q, a derivative of WZ4003 by removing a methoxy group, was found to be the most potential one with stronger inhibitory against NUAK1/2 enzyme activity, tumor cell proliferation and inducing apoptosis of tumor cells. By in vivo efficacy evaluations of colorectal SW480 xenografts, 9q suppresses tumor growth more effectively with an excellent safety profile in vivo and is therefore seen as a suitable candidate for further investigation.
- Yang, Huali,Wang, Xiaobing,Wang, Cheng,Yin, Fucheng,Qu, Lailiang,Shi, Cunjian,Zhao, Jinhua,Li, Shang,Ji, Limei,Peng, Wan,Luo, Heng,Cheng, Maosheng,Kong, Lingyi
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- Discovery of benzo[d]oxazole derivatives as the potent type-I FLT3-ITD inhibitors
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Fms-like tyrosine kinase 3 (FLT3) has been considered as a potential drug target for the treatment of acute myeloid leukemia (AML), because of its high and aberrant expression in AML patients, especially the patients with FLT3-ITD mutation. Initiating from a hit compound (IC50: 500 nM against FLT3-ITD), a series of compounds were designed and synthesized based on benzo[d]oxazole-2-amine scaffold to discover new potent FLT3-ITD inhibitors. During the medicinal chemistry works, flexible molecular docking was used to provide design rationale and study the binding modes of the target compounds. Through the mixed SAR exploration based on the enzymatic and cellular activities, compound T24 was identified with potent FLT3-ITD inhibitory (IC50: 0.41 nM) and anti-proliferative (IC50: 0.037 μM against MV4-11 cells) activities. And the binding mode of T24 with “DFG-in” FLT3 was simulated by a 20-ns molecular dynamics run, providing some insights into further medicinal chemistry efforts toward novel FLT3 inhibitors in AML therapy.
- Bao, Jiyin,Liu, Haichun,Zhi, Yanle,Yang, Wenqianzi,Zhang, Jiawei,Lu, Tao,Wang, Yue,Lu, Shuai
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- Cp*Co(iii) and Cu(OAc)2bimetallic catalysis for Buchwald-type C-N cross coupling of aryl chlorides and amines under base, inert gas & solvent-free conditions
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A strategy involving bimetallic catalysis with a combination of Cp?Co(CO)I2 and Cu(OAc)2 was used for performing Buchwald-type C-N coupling reactions of aryl chlorides with amines. The reactions proceeded at 100 °C to produce excellent yields of many of the desired C-N coupled products, in 4 h, under aerobic reaction conditions. The reactions were shown to run under base-free and solvent-free conditions, enabling this strategy to work efficiently for electron-withdrawing and base-sensitive functionalities. The presented methodology was found to be equally efficient for electron-donating functionalities as well as for primary (1°) and secondary (2°) aromatic and aliphatic amines. Moreover, the products were easily separated through the extractions of the organic aqueous layer, with this process chromatographic separations is not required.
- Srivastava, Avinash K.,Sharma, Charu,Joshi, Raj K.
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supporting information
p. 8248 - 8253
(2020/12/29)
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- Half-sandwich (η5-Cp?)Rh(iii) complexes of pyrazolated organo-sulfur/selenium/tellurium ligands: Efficient catalysts for base/solvent free C-N coupling of chloroarenes under aerobic conditions
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Three new pyrazolated chalcogenoether ligated Rh(iii) half-sandwich complexes (1-3) were synthesised by the thermal reaction of chalcogenoether (S, Se and Te) substituted 1H-pyrazole ligands (L1-L3) and [(η5-C5Me5)RhCl]2 in methanol. The complexes were fully characterised by various spectroscopic techniques, and the molecular structures of complexes 1 and2 were also established through single crystal X-ray crystallographic analysis, which indicates a pseudo-octahedral half-sandwich piano-stool geometry around the rhodium metal. All three complexes were found to be thermally stable and insensitive towards air and moisture. One mol% of Rh(iii) complexes (1-3) along with 10 mol% of Cu(OAc)2 were explored for the Buchwald-Hartwig type C-N coupling reactions of amine and aryl chloride. Good to excellent yields (89-92%) of the coupling products were obtained with seleno- and thio-ether functionalised pyrazolated Rh(iii) complexes (1 and 2), while an average yield (39%) was obtained with the telluro-ether functionalised complex (3). In contrast to the previously reported C-N coupling reactions the present reaction works under solvent- and base-free conditions, and the coupling reaction is accomplished in just 6 h with a high yield of the coupling product. The present methodology was also found to be efficient for a wide variety of functionalised aryl halides, and aliphatic or aromatic amines (1° and 2°). Moreover, the reaction also enables the C-N coupling of electron-withdrawing substrates and base-sensitive functionalities.
- Joshi, Raj Kumar,Sharma, Charu,Sharma, Kamal Nayan,Srivastava, Avinash Kumar
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supporting information
p. 3599 - 3606
(2020/06/10)
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- Amination of Aromatic Halides and Exploration of the Reactivity Sequence of Aromatic Halides
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A base-promoted amination of aromatic halides has been developed using a limited amount of dimethylformamide (DMF) or amine as an amino source. Various aryl halides, including F, Cl, Br, and I, have been successfully aminated in good to excellent yields. Although the amination of aromatic halides with amines or DMF is usually considered as an aromatic nucleophilic substitution (SNAr) process, and the reactivity of an aromatic halide is F > Cl > Br > I, the reactivity of aromatic halides in this system was found to be I > Br a‰ F > Cl. This protocol also showed a good regioselectivity for multihalogenated aromatics. This protocol is valuable for industrial application due to the simplicity of operation, the unrestricted availability of amino sources and aromatic halides, transition metal-free conditions, no requirement for solvent, and scalability.
- Yang, Chu,Zhang, Feng,Deng, Guo-Jun,Gong, Hang
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p. 181 - 190
(2019/01/10)
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- A palladium nanoparticle-catalyzed aryl-amine coupling reaction: High performance of aryl and pyridyl chlorides as the coupling partner
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Carbon nitride (CN)-supported nanosized palladium particles, Pd-CN, have been found to be an active catalyst system for the amination of aryl and pyridyl chloride moieties in the presence of dialkyl amine under mild reaction conditions. The recyclability study of the reaction shows the stable performance of the catalyst without a significant loss of catalytic activity for a couple of cycles.
- Nandi, Debkumar,Islam, Rafique Ul,Devi, Nishu,Siwal, Samarjeet,Mallick, Kaushik
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supporting information
p. 812 - 816
(2018/02/06)
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- Synthesis of functionalized 4-nitroanilines by ring transformation of dinitropyridone with enaminones
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2-Functionalized 4-nitroanilines were readily synthesized by ring transformation using 3,5-dinitro-2-pyridone and enaminones prepared from 1,3-dicarbonyl compounds and amines. Modification of the amino group and the ortho-position could be achieved by sim
- Naito, Saki,Yokoyama, Soichi,Asahara, Haruyasu,Nishiwaki, Nagatoshi
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supporting information
p. 4699 - 4702
(2017/11/21)
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- Discovery of Potent, Selective Stem Cell Factor Receptor/Platelet Derived Growth Factor Receptor Alpha (c-KIT/PDGFRα) Dual Inhibitor for the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs)
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Stem cell factor receptor (c-KIT) and platelet derived growth factor receptor alpha (PDGFRα) kinases play an important role in gastrointestinal stromal tumors (GISTs). Here, we have discovered an c-KIT/PDGFRα dual inhibitor, compound 31, with single-digit nanomolar potency against c-KIT and PDGFRα. Compared to Imatinib (1), 31 showed better antiproliferative efficacy against various TEL-c-KIT/PDGFRα-BaF3 isogenic cells, including three 1-resistant BaF3 cell lines, as well as against GIST-T1 and GIST-882 cell lines. Furthermore, compound 31 showed a good KinomeScan selectivity (468 kinases) (S score (1) = 0.01 at 1 μM concentration), good metabolic stability in liver microsomes, and no hERG inhibitory activity. It was worth noting that 31 inhibited GIST-T1 tumor growth (TGI = 81.5%) and even the BaF3-TEL-cKIT-T670I tumor progression (TGI = 41.9%, 1-resistant GISTs) at a dosage of 100 mg/kg/day without exhibiting apparent toxicity.
- Lu, Yanli,Mao, Fei,Li, Xiaokang,Zheng, Xinyu,Wang, Manjiong,Xu, Qing,Zhu, Jin,Li, Jian
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supporting information
p. 5099 - 5119
(2017/06/28)
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- Combination of 4-anilinoquinazoline, arylurea and tertiary amine moiety to discover novel anticancer agents
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In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors.
- Zuo, Sai-Jie,Zhang, Sai,Mao, Shuai,Xie, Xiao-Xiao,Xiao, Xue,Xin, Min-Hnag,Xuan, Wei,He, Yuan-Yuan,Cao, Yong-Xiao,Zhang, San-Qi
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p. 179 - 190
(2015/12/31)
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- Magnetic silica supported copper: A modular approach to aqueous Ullmann-type amination of aryl halides
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One-pot synthesis of a magnetic silica supported copper catalyst has been described via in situ generated magnetic silica (Fe3O 4@SiO2); the catalyst can be used for the efficacious amination of aryl halides in aqueous medium under microwave irradiation.
- Nasir Baig,Varma, Rajender S.
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p. 6568 - 6572
(2014/02/14)
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- TGF-beta SIGNAL TRANSDUCTION INHIBITOR
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The present invention provides a compound represented by the following formula (I) or a physiologically acceptable salt thereof, and use thereof for the prophylaxis or treatment of TGF-β-related diseases: wherein Y is a hydrogen atom and the like; R2 is and the like; R3 is —NR8—R9— and the like; R4, R5, R6 and R7 are the same or different and each is a hydrogen atom and the like; and X is and the like.
- -
-
Paragraph 0219; 0220; 0221; 0222
(2013/03/26)
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- CuI/DMPAO-catalyzed N-arylation of acyclic secondary amines
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DMPAO has been found to be a powerful ligand to enable copper-catalyzed coupling of aryl halides with aliphatic acyclic secondary amines take place under relatively mild conditions, and coupling of aryl halides with primary amines and cyclic secondary amines proceeds at low catalyst loading.
- Zhang, Yu,Yang, Xinye,Yao, Qizheng,Ma, Dawei
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supporting information; experimental part
p. 3056 - 3059
(2012/07/28)
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- Nano ceria catalyzed Ullmann type coupling reactions
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Ullmann type intermolecular coupling of aryl halide with hetero-aromatic compounds, such as phenols, amines, and thiophenols are key reactions for the formation of carbon-heteroatom bond in organic synthesis. We report a robust and novel method that provides an efficient and economic route for the synthesis of O, N, and S-arylation via Ullman coupling by using nano cerium oxide (ceria, CeO2). CeO2 is a cheaper catalyst compared to related copper based catalysts. This method provides a wide range of substrate applicability in the case of phenols and amines. Less reactive chlorobenzene substituted with strong electron withdrawing groups such as 4-nitrochlorobenzene and 4-cyanochlorobenzene favor the reaction. This protocol avoids the use of ligand and gives arylated product in satisfactory yields.
- Agawane, Sandeep M.,Nagarkar, Jayashree M.
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experimental part
p. 5220 - 5223
(2011/10/12)
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- Oxidative coupling of N,N-Dialkylanilines using iodic acid and sodium nitrite
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A new reagent system, a combination of iodic acid and sodium nitrite has been investigated for oxidative coupling of N,N-disubstituted anilines. A facile para-selective coupling occurs to give benzidines at room temperature in water as a solvent. A tentative mechanism is proposed with some supporting experiments.
- Huddar, Sameerana N.,Mahajan, Ulhas S.,Akamanchi, Krishnacharya G.
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experimental part
p. 808 - 809
(2011/01/07)
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- Ce(SO4)2-mediated nitration of N,N-dialkylanilines with NaNO2 in water
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Ce(SO4)2-mediated nitration of N,N-dialkylanilines with NaNO2 using water as the solvent has been achieved in good to excellent yields. The nitrating reaction proceeded smoothly at ambient temperature. Copyright Taylor & Francis Group, LLC.
- Yang, Xianghua,Xi, Chanjuan
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p. 3381 - 3392
(2008/02/12)
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- Highly chemoselective nitration of aromatic amines using the Ph3P/Br2/AgNO3 system
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The use of PPh3/Br2/AgNO3 provides a new reagent system for the novel and highly chemoselective nitration of aromatic amines under mild reaction conditions.
- Iranpoor, Nasser,Firouzabadi, Habib,Nowrouzi, Najmeh,Firouzabadi, Dena
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p. 6879 - 6881
(2007/10/03)
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- Regioselective nitration of N,N-dialkylanilines using cerium(IV) ammonium nitrate in acetonitrile
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A highly regioselective and inexpensive nitration of N,N-dialkylanilines by cerium(IV) ammonium nitrate (CAN) in acetonitrile under room temperature to yield p-nitryl-N,N-dialkylanilines in good yields was reported.
- Yang, Xianghua,Xi, Chanjuan,Jiang, Yanfeng
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p. 8781 - 8783
(2007/10/03)
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- Supported bismuth(III) nitrate on silica sulfuric acid as useful reagent for nitration of aromatic compounds under solvent-free conditions
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A number of aromatic compounds were nitrated to the corresponding nitroaromatic derivatives with the use of supported bismuth(III) nitrate on silica sulfuric acid under solvent-free conditions.
- Hajipour,Zarei,Ruoho
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p. 1493 - 1495
(2007/10/03)
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- Study of ultrasound promoted aromatic nucleophilic substitution of halobenzenes with amines
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The sonochemical nucleophilic aromatic substitution of substituted haloarenes with different amines were studied. The reaction course was found to be strongly depended on basicity, bulkiness, and boiling point of amines as well as on the electron-withdrawing property of the substituents.
- Meciarova, Maria,Toma, Stefan,Podlesna, Jana,Kiripolsky, Michal,Cisarova, Ivana
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- Alkylation of nitroaromatics with trialkylborane
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A novel, facile, aromatic substitution reaction of nitroaromatics is described. When p-dinitrobenzene (1) is treated with trialkylborane in the presence of potassium tert-butoxide, it furnishes p-alkylnitrobenzene (2) in high yield. A tentative mechanism is suggested involving alkyl radicals and radical anions of the nitroaromatic substrate.
- Shifman, Anna,Palani, Namasivayam,Hoz, Shmaryahu
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p. 944 - 945
(2007/10/03)
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- Amination of aryl bromides catalysed by supported palladium
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Palladium particles immobilised onto a metal oxide support or Pd(0), Pd(II) and [Pd(NH3)4]2+ in NaY zeolite have been prepared and characterised. They exhibit a good activity towards the amination of aryl bromides using secondary amines such as piperidine and diethyl amine with a good regio-selectivity for these reactions. Low Pd concentrations (1 mol%) are required to observe a reasonable regio-selectivity. The catalysts can easily be separated from the reaction mixture (filtration) and reused without loss of activity and selectivity. The electronic nature of the aryl halides plays an important role for both the reaction yields and the regio-control of the reaction. It depends on the relation of the direct amination via a benzyne intermediate versus the Pd-catalysed route.
- Djakovitch, Laurent,Wagner, Michael,Koehler, Klaus
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p. 225 - 234
(2007/10/03)
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- New experiments in the reductive N-alkylation and N-peralkylation of aromatic amines
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Some secondary and primary aromatic amines were variously N-alkylated and N-peralkylated by the aldehyde-sodium borohydride procedure in acidic aqueous solution. The procedure lends itself to the α-mono and α,α1-dideuterium labelling of the new N-substituent(s).
- Verardo,Giumanini,Strazzolini
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p. 609 - 627
(2007/10/02)
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- Aromatic Nucleophilic Substitution of Halobenzenes with Amines under High Pressure
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The nucleophilic substitution reactions of aromatic halides having electron-attracting groups on ortho or para position with various primary and secondary amines were accelerated by high pressure to give the corresponding N-substituted anilines in high yields.The bulkiness of amines affects its reactivity to lower the yields of the products.Although the secondary amines are usually less reactive than primary amines, cyclic secondary amines such as morpholine, piperidine, and pyrrolidine were found very reactive. 1,4-Diazabicyclooctane and quinuclidine gave N-quarternary ammonium halides in high yields in contrast to the low reactivity of acyclic tertiary amines.Dichloro- and trichloro-nitrobenzenes also react with diethylamine, pyrrolidine, and morpholine to give mono-, di-, and trisubstitution products depending upon the amount of amine and the position of nitro group in these chlorides.
- Ibata, Toshikazu,Isogami, Yasushi,Toyoda, Jiro
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- Acyclic Tertiary Amines as Nucleophiles in Substitution Reactions of Aromatic and Heteroaromatic Halides
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Even acyclic tertiary amines such as triethylamine, tri-n-propylamine and tri-n-butylamine, which have been believed to be inert to aromatic and heteroaromatic halides, underwent SNAr reactions with aromatic and heteroaromatic halides to give the dialkylamino derivatives; in the case of monocyclic amines like N-methylpyrrolidine and N-methylpiperidine, the dealkylation being regioselective.
- Matsumoto, Kiyoshi,Hashimoto, Shiro,Otani, Shinichi
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p. 306 - 307
(2007/10/02)
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- Nucleophilic Substitution of Aromatic Halides with Amines under High Pressure
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The reaction of aromatic chlorides, bromides and iodides with various primary or secondary amines in a tetrahydrofuran solution under high pressure of 6-12 kbar gave the corresponding secondary and tertiary aromatic amines. 1,4-Diazabicyclooctane and quinuclidine gave N-aryl quaternary ammonium halides in high yields in contrast to the low reactivity of acyclic tertiary amines.
- Ibata, Toshikazu,Isogami, Yasushi,Toyoda, Jiro
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p. 1187 - 1190
(2007/10/02)
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- PALLADIUM-CATALYZED AROMATIC AMINATION OF ARYL BROMIDES WITH N,N-DIETHYLAMINO-TRIBUTYLTIN
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The reaction of N,N-diethylamino-tributyltin with aryl bromides in the presence of a catalytic amount of PdCl2(o-tolyl3P)2 gave N,N-diethylaminobenzene derivatives.The reaction is a new kind of amination different from ones through aryne or SRN1 mechanism.
- Kosugi, Masanori,Kameyama,Masayuki,Migita, Toshihiko
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p. 927 - 928
(2007/10/02)
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- Nucleophilic Reaction upon Electron-deficient Pyridone Derivatives. IV. Ring Transformation of 1-Substituted 3,5-Dinitro-2-pyridones with Ketones in the Presence of Amines
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Ring transformation of 1-substituted 3,5-dinitro-2-pyridones with 1,3-disubstituted acetones in the presence of secondary or primary amines gave p-nitroaniline derivatives and N-substituted 2-nitroacetamide.Two types of enamine intermediates, 2-azabicyclononene derivatives and N-substituted 2-(5-amino-2-nitro-2,4-cyclohexadienyl)-2-nitroacetamides were isolated and characterized.The course of the base-catalyzed reaction is interpreted.
- Matsumura, Eizo,Tohda, Yasuo,Ariga, Masahiro
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p. 2174 - 2180
(2007/10/02)
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