- Effects of the tumor-vasculature-disrupting agent verubulin and two heteroaryl analogues on cancer cells, endothelial cells, and blood vessels
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Two analogues of the discontinued tumor vascular-disrupting agent verubulin (Azixa, MPC-6827, 1) featuring benzo-1,4-dioxan-6-yl (compound 5 a) and N-methylindol-5-yl (compound 10) residues instead of the para-anisyl group on the 4-(methylamino)-2-methylquinazoline pharmacophore, were prepared and found to exceed the antitumor efficacy of the lead compound. They were antiproliferative with single-digit nanomolar IC50 values against a panel of nine tumor cell lines, while not affecting nonmalignant fibroblasts. Indole 10 surpassed verubulin in seven tumor cell lines including colon, breast, ovarian, and germ cell cancer cell lines. In line with docking studies indicating that compound 10 may bind the colchicine binding site of tubulin more tightly (Ebind=-9.8 kcal mol-1) than verubulin (E bind=-8.3 kcal mol-1), 10 suppressed the formation of vessel-like tubes in endothelial cells and destroyed the blood vessels in the chorioallantoic membrane of fertilized chicken eggs at nanomolar concentrations. When applied to nude mice bearing a highly vascularized 1411HP germ cell xenograft tumor, compound 10 displayed pronounced vascular-disrupting effects that led to hemorrhages and extensive central necrosis in the tumor. Variations on a promising theme: Tumor blood vessels are a good therapeutic target because they are fundamentally different from normal vasculature. This study shows that vascular-disrupting agents derived from verubulin have enhanced selectivity for cancer cells and lower general in vivo toxicity, yet they retain the strong antivascular activity of the lead compound.
- Mahal, Katharina,Resch, Marcus,Ficner, Ralf,Schobert, Rainer,Biersack, Bernhard,Mueller, Thomas
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Read Online
- A Metal-Free Direct Arene C?H Amination
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The synthesis of aryl amines via the formation of a C?N bond is an essential tool for the preparation of functional materials, active pharmaceutical ingredients and bioactive products. Usually, this chemical connection is only possible by transition metal-catalyzed reactions, photochemistry or electrochemistry. Here, we report a metal-free arene C?H amination using hydroxylamine derivatives under benign conditions. A charge transfer interaction between the aminating reagents TsONHR and the arene substrates enables the chemoselective amination of the arene, even in the presence of various functional groups. Oxygen was crucial for an effective conversion and its accelerating role for the electron transfer step was proven experimentally. In addition, this was rationalized by a theoretical study which indicated the involvement of a dioxygen-bridged complex with a “Sandwich-like” arrangement of the aromatic starting materials and the aminating agents at the dioxygen molecule. (Figure presented.).
- Wang, Tao,Hoffmann, Marvin,Dreuw, Andreas,Hasagi?, Edina,Hu, Chao,Stein, Philipp M.,Witzel, Sina,Shi, Hongwei,Yang, Yangyang,Rudolph, Matthias,Stuck, Fabian,Rominger, Frank,Kerscher, Marion,Comba, Peter,Hashmi, A. Stephen K.
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supporting information
p. 2783 - 2795
(2021/04/05)
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- Ruthenium(ii) complexes with N-heterocyclic carbene-phosphine ligands for theN-alkylation of amines with alcohols
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Metal hydride complexes are key intermediates forN-alkylation of amines with alcohols by the borrowing hydrogen/hydrogen autotransfer (BH/HA) strategy. Reactivity tuning of metal hydride complexes could adjust the dehydrogenation of alcohols and the hydrogenation of imines. Herein we report ruthenium(ii) complexes with hetero-bidentate N-heterocyclic carbene (NHC)-phosphine ligands, which realize smart pathway selection in theN-alkylated reactionviareactivity tuning of [Ru-H] species by hetero-bidentate ligands. In particular, complex6cbwith a phenyl wingtip group and BArF?counter anion, is shown to be one of the most efficient pre-catalysts for this transformation (temperature is as low as 70 °C, neat conditions and catalyst loading is as low as 0.25 mol%). A large variety of (hetero)aromatic amines and primary alcohols were efficiently converted into mono-N-alkylated amines in good to excellent isolated yields. Notably, aliphatic amines, challenging methanol and diamines could also be transformed into the desired products. Detailed control experiments and density functional theory (DFT) calculations provide insights to understand the mechanism and the smart pathway selectionvia[Ru-H] species in this process.
- Huang, Ming,Li, Yinwu,Lan, Xiao-Bing,Liu, Jiahao,Zhao, Cunyuan,Liu, Yan,Ke, Zhuofeng
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supporting information
p. 3451 - 3461
(2021/05/03)
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- Effect of the ancillary ligand in N-heterocyclic carbene iridium(III) catalyzed N-alkylation of amines with alcohols
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A series of air-stable N-heterocyclic carbene (NHC) Ir(III) complexes (Ir1-6), bearing various combinations of chlorine, pyridine and NHC ligands, were assayed for the N-alkylation of amines with alcohols. It was found that Ir3, with two monodentate 1,3-bis-methyl-imidazolylidene (IMe) ligands, emerged as the most active complex. A large variety of amines and primary alcohols were efficiently converted into mono-N-alkylated amines in 53–96% yields. As a special highlight, for the challenging MeOH, selective N-monomethylation could be achieved using KOH as a base under an air atmosphere. Moreover, this catalytic system was successfully applied to the gram-scale synthesis of some valuable compounds.
- Feng, Xinshu,Huang, Ming
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- Simple RuCl3-catalyzed N-Methylation of Amines and Transfer Hydrogenation of Nitroarenes using Methanol
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Methanol is a potential hydrogen source and C1 synthon, which finds interesting applications in both chemical synthesis and energy technologies. The effective utilization of this simple alcohol in organic synthesis is of central importance and attracts scientific interest. Herein, we report a clean and cost-competitive method with the use of methanol as both C1 synthon and H2 source for selective N-methylation of amines by employing relatively cheap RuCl3.xH2O as a ligand-free catalyst. This readily available catalyst tolerates various amines comprising electron-deficient and electron-donating groups and allows them to transform into corresponding N-methylated products in moderate to excellent yields. In addition, few marketed pharmaceutical agents (e. g., venlafaxine and imipramine) were also successfully synthesized via late-stage functionalization from readily available feedstock chemicals, highlighting synthetic value of this advanced N-methylation reaction. Using this platform, we also attempted tandem reactions with selected nitroarenes to convert them into corresponding N-methylated amines using MeOH under H2-free conditions including transfer hydrogenation of nitroarenes-to-anilines and prepared drug molecules (e. g., benzocaine and butamben) as well as key pharmaceutical intermediates. We further enable one-shot selective and green syntheses of 1-methylbenzimidazole using ortho-phenylenediamine (OPDA) and methanol as coupling partners.
- Sarki, Naina,Goyal, Vishakha,Tyagi, Nitin Kumar,Puttaswamy,Narani, Anand,Ray, Anjan,Natte, Kishore
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p. 1722 - 1729
(2021/04/19)
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- Synthesis of: N -methylated amines from acyl azides using methanol
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The transformation of acyl azide derivatives into N-methylamines was developed using methanol as the C1 source via the one-pot Curtius rearrangement and borrowing hydrogen methodology. Following this protocol, various functionalised N-methylated amines were synthesized using the (NNN)Ru(ii) complex from carboxylic acids via an acyl azide intermediate. Several kinetic studies and DFT calculations were carried out to support the mechanism and also to determine the role of the Ru(ii) complex and base in this transformation.
- Chakrabarti, Kaushik,Dutta, Kuheli,Kundu, Sabuj
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p. 5891 - 5896
(2020/08/21)
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- Selective N -monomethylation of primary anilines with the controllable installation of N -CH2D, N -CHD2, and N -CD3units
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The selective N-monomethylation of primary anilines was realized by the use of the Me3N-BH3/N,N-dimethylformamide (DMF) system as the methyl source. This method also allows for the controllable introduction of N-CH2D, N-CHD2, and N-CD3 units with high lev
- Meng, Jing,Wang, Yi-Feng,Wang, Zhijuan,Xia, Hui-Min,Xu, Ai-Qing,Zhang, Feng-Lian
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supporting information
p. 4922 - 4926
(2020/07/30)
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- Palladium-Catalyzed Methylation of Nitroarenes with Methanol
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A procedure for the synthesis of N-methyl-arylamines directly from nitroarenes using methanol as green methylating agent was developed. The key to success is the use of a specific catalyst system consisting of palladium acetate and the ligand 1-[2,6-bis(isopropyl)phenyl]-2-[tert-butyl(2-pyridinyl)phosphino]-1H-Imidazole (L1). The generality of this protocol is demonstrated in the synthesis of more than 20 N-methyl-arylamines under comparably mild conditions. Combining this novel methodology with subsequent coupling processes using the same catalyst allows for efficient diversification of aromatic nitro compounds to a broad variety of amines including drug molecules.
- Wang, Lin,Neumann, Helfried,Beller, Matthias
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supporting information
p. 5417 - 5421
(2019/04/04)
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- Commercial Pd/C-Catalyzed N-Methylation of Nitroarenes and Amines Using Methanol as Both C1 and H2 Source
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Herein, we report commercially available carbon-supported-palladium (Pd/C)-catalyzed N-methylation of nitroarenes and amines using MeOH as both a C1 and a H2 source. This transformation proceeds with high atom-economy and in an environmentally friendly way via borrowing hydrogen mechanism. A total of >30 structurally diverse N-methylamines, including bioactive compounds, were selectively synthesized with isolated yields of up to 95%. Furthermore, selective N-methylation and deuteration of nimesulide, a nonsteroidal anti-inflammatory drug, were realized through the late-stage functionalization.
- Goyal, Vishakha,Gahtori, Jyoti,Narani, Anand,Gupta, Piyush,Bordoloi, Ankur,Natte, Kishore
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p. 15389 - 15398
(2019/12/04)
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- Catalytic Hydrogenation of Carboxamides with a Bifunctional Cp Ru Catalyst Bearing an Imidazol-2-ylidene with a Protic Aminoethyl Side Chain
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Synthesis of a Cp Ru complex bearing an NH 2 -functionalized N -heterocyclic carbene (C-N H) was achieved by treatment of CpRuBr(isoprene) with an equimolar amount of a silver complex, which was generated from Ag 2 O and 1-(2-aminoethyl)-3-methylimidazolium bromide, in CH 3 CN at room temperature. The new CpRuBr(C-N H) complex showed a higher catalytic performance than the related CpRuCl(P-N H) and CpRuCl(N-N H) complexes. In the reaction of N -arylcarboxamides, the amine products were obtained in satisfactory yields under mild temperature conditions.
- Ikariya, Takao,Kawano, Teruhiro,Kayaki, Yoshihito,Watari, Ryo
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p. 2542 - 2547
(2019/06/08)
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- Photodriven Photocatalyst/Metal-Free Direct C-C/C-N Bond Formation: Synthesis of Indoles via EDA Complexes
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The photodriven direct C-C/C-N bond formation initiated by electron donor-acceptor (EDA) complexes for the synthesis of indoles has been accomplished via [3+2] annulations of secondary arylamines with alkynes using IC4F9 as oxidants in the absence of any photocatalysts and metals. This green transformation exhibits the advantages of operational simplicity, good functional tolerances, and mild reaction conditions. The in situ generated EDA complexes derived from arylamines with alkynes were characterized by UV-vis absorption spectrometry and NMR titration experiments.
- Guo, Wei,Tao, Kailiang,Xie, Zhen,Cai, Liuhuan,Zhao, Mingming,Tan, Wen,Liu, Gongping,Mei, Weijie,Deng, Ling,Fan, Xiaolin,Zheng, Lvyin
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p. 14168 - 14178
(2019/10/16)
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- Room temperature N-heterocyclic carbene manganese catalyzed selective N-alkylation of anilines with alcohols
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The first example of room temperature non-noble metal homogeneous system catalyzed selective N-alkylation of anilines with alcohols by a bis-NHC manganese complex is presented. This system was applied to a large range of alcohols and anilines, including biologically relevant motifs and challenging methanol. Experimental and computational studies suggest an outer-sphere mechanism for this NHC-Mn system.
- Huang, Ming,Li, Yukui,Li, Yinwu,Liu, Jiahao,Shu, Siwei,Liu, Yan,Ke, Zhuofeng
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supporting information
p. 6213 - 6216
(2019/06/07)
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- Well-Defined Phosphine-Free Iron-Catalyzed N-Ethylation and N-Methylation of Amines with Ethanol and Methanol
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An iron(0) complex bearing a cyclopentadienone ligand catalyzed N-methylation and N-ethylation of aryl and aliphatic amines with methanol or ethanol in mild and basic conditions through a hydrogen autotransfer borrowing process is reported. A broad range of aromatic and aliphatic amines underwent mono- or dimethylation in high yields. DFT calculations suggest molecular hydrogen acts not only as a reducing agent but also as an additive to displace thermodynamic equilibria.
- Lator, Alexis,Gaillard, Sylvain,Poater, Albert,Renaud, Jean-Luc
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supporting information
p. 5985 - 5990
(2018/10/02)
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- Mono-N-methylation of anilines with methanol catalyzed by a manganese pincer-complex
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The selective mono-N-methylation of anilines derivatives was achieved under mild conditions using inexpensive methanol as C1 source. Under hydrogen borrowing conditions, using a tridentate PN3P manganese pre-catalyst (5?mol%), a catalytic amount of base (20?mol%), for 24?h at 120?°C, a large variety of anilines derivatives was methylated in good to excellent yield. Mechanistic investigations allowed us to isolate and characterize by X-ray diffraction studies a de-aromatized manganese intermediate.
- Bruneau-Voisine, Antoine,Wang, Ding,Dorcet, Vincent,Roisnel, Thierry,Darcel, Christophe,Sortais, Jean-Baptiste
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- INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
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Compounds of Formula I with activity against HIV, including pharmaceutical compositions and methods for using these compounds in treating human immunodeficiency virus (HIV) infection, are set forth: Formula :(I)
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Page/Page column 45; 46
(2015/05/06)
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- Selective methylation of amines with carbon dioxide and H2
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Put a label on it: Carbon dioxide with H2 is shown to be an efficient and selective methylation reagent for aromatic and aliphatic amines (see scheme; acac=acetylacetonate, triphos = 1,1,1- tris(diphenylphosphanylmethyl)ethane). A variety of functionalized amines including 13C-labelled drugs were obtained with good yields and functional-group tolerance. Copyright
- Li, Yuehui,Sorribes, Ivan,Yan, Tao,Junge, Kathrin,Beller, Matthias
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supporting information
p. 12156 - 12160
(2013/12/04)
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- COMPOUNDS AND METHODS
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Disclosed are compounds having formula I, wherein X1, X2, X3, R1, R2, R3, R4, R5, Y, A, Z, L, m and n are as defined herein, and methods of making and using the same.
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Page/Page column 57; 58; 62
(2013/03/26)
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- ANTIVIRAL COMPOUNDS
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The present invention relates to a compound of formula: (I) or a pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same, a method for treating or preventing a viral infection such as HIV using the same.
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Paragraph 0143
(2013/03/26)
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- NOVEL ANTIVIRAL COMPOUNDS
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The present invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same, a method for treating or preventing a viral infection such as HIV using the same.
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Page/Page column 48-49
(2012/05/31)
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- Synthesis of N-methylphenanthridinone derivatives fused with a silacyclohexane ring by radical reaction using tributyltin hydride
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Radical reaction of (N-methyl-7-bromo-2,2-dimethyl-2-silatetralin-6-ylamino)veratramide (8a) and -piperonamides (8b) in boiling benzene using tributyltin hydride and AIBN gave two kinds of N-methylphenanthridinone derivatives (15 and 16), which were cyclized at 6- and 2-positions of aroylic acid moiety. On the other hand, similar reaction of N-methyl-N-(2-bromoveratryl and 2-bromopiperonyl)-2,2-dimethyl-2-silatetralin-6-carboxamides (14) produced N-methylphenanthridinone deivatives (17) as each sole product, in which cyclization occurred at 5-position of 2-silatetralin moiety.
- Hoshino, Yuya,Hoshino, Osamu
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p. 659 - 666
(2007/10/03)
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- Novel tricyclic dihydro-quinoline derivatives, method for preparing same and pharmaceutical compositions containing the same
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A compound of formula (I): wherein: represents a single or double bond, represents a ring system selected from R9a, R9b, R9c, X and Y are as defined in the description, R1 represents a group selected from hydrog
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Page/Page column 7
(2010/02/08)
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