- N-Phenyl-1,2,3,4-tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β-Hydroxysteroid Dehydrogenase 1 Inhibitors
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17β-Hydroxysteroid dehydrogenases catalyse interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less-active estrone to estradiol, and inhibitors have therapeutic potential in estrogen-dependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N-phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ) template was pursued by using Pomeranz-Fritsch-Bobbitt, Pictet-Spengler and Bischler-Napieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structure-activity relationships are discussed. THIQs possessing a 6-hydroxy group, lipophilic substitutions at the 1- or 4-positions in combination with N-4′-chlorophenyl substitution were most favourable for activity. Of these, one compound had an IC50 of ca. 350 nM as a racemate, testifying to the applicability of this novel approach.
- Mottinelli, Marco,Sinreih, Ma?a,Ri?ner, Tea L.,Leese, Mathew P.,Potter, Barry V. L.
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p. 259 - 291
(2020/12/07)
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- Iron-Catalyzed Enantioselective Radical Carboazidation and Diazidation of α,β-Unsaturated Carbonyl Compounds
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Azidation of alkenes is an efficient protocol to synthesize organic azides which are important structural motifs in organic synthesis. Enantioselective radical azidation, as a useful strategy to install a C-N3 bond, remains challenging due to the inherently instability and unique structure of radicals. Here, we disclose an efficient enantioselective radical carboazidation and diazidation of α,β-unsaturated ketones and amides catalyzed by chiral N,N′-dioxide/Fe(OTf)2 complexes. An array of substituted alkenes was transformed to the corresponding α-azido carbonyl derivatives in good to excellent enantioselectivities, benefiting the preparation of chiral α-amino ketones, vicinal amino alcohols, and vicinal diamines. Control experiments and mechanistic studies proved the radical pathway in the reaction process. The DFT calculations showed that the azido transferred to the radical intermediate via an intramolecular five-membered transition state with the internal nitrogen of the Fe-N3 species.
- Dong, Shunxi,Feng, Xiaoming,He, Jun,Liu, Wen,Liu, Xiaohua,Pu, Maoping,Wu, Yun-Dong,Zhang, Tinghui
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supporting information
p. 11856 - 11863
(2021/08/16)
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- Synthesis of Benzo[ b]furans by Intramolecular C-O Bond Formation Using Iron and Copper Catalysis
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One-pot processes for the synthesis of benzo[b]furans from 1-aryl- or 1-alkylketones using nonprecious transition metal catalysts have been developed. Regioselective iron(III)-catalyzed halogenation of the aryl ring, followed by iron- or copper-catalyzed O-arylation allowed the synthesis of various structural analogues, including the benzo[b]furan-derived natural products corsifuran C, moracin F, and caleprunin B.
- Henry, Martyn C.,Sutherland, Andrew
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supporting information
p. 2766 - 2770
(2020/03/30)
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- Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation
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A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N-or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.
- Henry, Martyn C.,Senn, Hans Martin,Sutherland, Andrew
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p. 346 - 364
(2019/01/08)
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- Rh/Lewis Acid Catalyzed Regio-, Diastereo- and Enantioselective Addition of 2-Acyl Imidazoles with Allenes
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A highly regio-, diastereo- and enantioselective addition of 2-acyl imidazoles or 2-acyl pyridines with allenes promoted by Rh/Lewis acid synergistically catalytic system is described. This atom economic approach leads to the formation of the branched allylic alkylated products including acyclic quaternary all-carbon stereogenic centres in good yields with good to excellent diastereo- and enantioselectivities. Kinetic studies reveal that the rate-determining step in this process is the oxidative addition of Rh(I) with C—H bond.
- Bora, Pranjal P.,Sun, Gui-Jun,Zheng, Wei-Feng,Kang, Qiang
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supporting information
p. 20 - 24
(2017/11/23)
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- 'Wake-Up Call of A Sleeping Beauty': Straightforward Synthesis of Functionalized β-(2-Pyridyl) Ketones from 2,6-Lutidine
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β-(2-Pyridyl) ketones are a unique class of heterocycles with valuable physicochemical properties and emerging relevance as pharmacophores. Herein we report a one-step process for the preparation of various substituted β-(2-pyridyl) ketones from the common starting material, 2,6-lutidine. Furthermore, we demonstrate the utility of this building block by synthesizing of a small set of antimalarial natural products.
- Bouchez, Laure C.,Gerbeaux, Cyril,Rusch, Marion,Patoor, Maude,Livendahl, Madeleine,Press, Neil J.
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supporting information
p. 1219 - 1223
(2017/06/13)
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- TiCl4-promoted tandem carbonyl or imine addition and friedel-crafts cyclization: Synthesis of benzo-fused oxabicyclooctanes and nonanes
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A new and convenient synthesis of benzo-fused 8-oxabicyclo[3.2.1]octane and 9-oxabicyclo[4.2.1]nonane derivatives are described. The reaction involved a TiCl4-mediated tandem carbonyl or imine addition followed by a Friedel-Crafts cyclization t
- Ghosh, Arun K.,Martyr, Cuthbert D.,Xu, Chun-Xiao
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supporting information; experimental part
p. 2002 - 2005
(2012/06/01)
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- TETRACYCLIC HETEROCYCLE COMPOUNDS FOR TREATING HEPATITIS C VIRAL INFECTION
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Tetracyclic heterocycle compounds of formula (I) and pharmaceutically acceptable salts thereof are provided, wherein A, A', G, R1, R15, U, V, V', W, W, X, X', Y and Y' are as defined in the invention. The pharmaceutical compositions comprising these compounds and the use of the compounds for treating hepatitis C virus (HCV) infection are also provided.
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Page/Page column 116
(2012/04/17)
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- Copper(II)-catalyzed meta-selective direct arylation of α-aryl carbonyl compounds
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Strong competition: A method for the meta-selective arylation of the highly versatile α-aryl carbonyl motif using diaryliodonium salts is described. In this CuII-catalyzed process the remote carbonyl group is capable of overpowering even strongly para-directing functionalities to form the elusive meta-products (see scheme). Remarkably, the arylation process can also operate under metal-free conditions.
- Duong, Hung A.,Gilligan, Ruth E.,Cooke, Michael L.,Phipps, Robert J.,Gaunt, Matthew J.
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supporting information; experimental part
p. 463 - 466
(2011/03/16)
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- Sequential rhodium-, silver-, and gold-catalyzed synthesis of fused dihydrofurans
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A triple cascade process was developed for the rapid synthesis of polycyclic benzo-fused dihydrofurans. The first step is a rhodium-catalyzed cyclopropanation of α-aryldiazoketones with alkenes. This is followed by a silver-catalyzed ring expansion to dih
- Wang, Hengbin,Denton, Justin R.,Davies, Huw M. L.
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supporting information; experimental part
p. 4316 - 4319
(2011/10/05)
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- NOVEL DIHYDROPYRIMIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 152
(2011/04/24)
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- Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists
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We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC50/s
- Mabire, Dominique,Coupa, Sophie,Adelinet, Christophe,Poncelet, Alain,Simonnet, Yvan,Venet, Marc,Wouters, Ria,Lesage, Anne S. J.,Van Beijsterveldt, Ludy,Bischoff, Fran?ois
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p. 2134 - 2153
(2007/10/03)
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- ALPHA, ALPHA DIALKYLBENZYL DERIVATIVES
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The invention concerns (alpha),(alpha)-dialkylbenzyl derivatives of the formula I wherein Ar1 is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur; A1 is a direct link to X1 or is (1-3C)alkylene; X1 is oxy, thio, sulphinyl or sulphonyl; the phenylene group may optionally bear one or two substituents R3; each of R1 and R2, which may be the same or different, is (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, fluoro-(1-4C)alkyl, phenyl or phenyl-(1-4C)alkyl, provided that both of R1 and R2 are not methyl or fluoromethyl; and Q is cyano, amino, nitro, formyl, (1-4C)alkoxy, thiazolyl or (2-4C)alkanoyl; or a pharmaceutically-acceptable salt thereof; processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors
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