- Selective Methylation of Amides, N-Heterocycles, Thiols, and Alcohols with Tetramethylammonium Fluoride
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We herein disclose the use of tetramethylammonium fluoride (TMAF) as a direct and selective methylating agent of a variety of amides, indoles, pyrroles, imidazoles, alcohols, and thiols. The method is characterized by operational simplicity, wide scope, and ease of purification. Our computational studies suggest a concerted methylation-deprotonation as the preferred reaction pathway.
- Cheng, Hong-Gang,Pu, Maoping,Kundu, Gourab,Schoenebeck, Franziska
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supporting information
p. 331 - 334
(2019/12/30)
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- Design and synthesis of thiadiazolo-carboxamide bridged β-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity
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The conjoining of salient pharmacophoric properties directing the development of prominent cytotoxic agents was executed by constructing thiadiazolo-carboxamide bridged β-carboline-indole hybrids. On the evaluation of in vitro cytotoxic potential, 12c exhibited prodigious cytotoxicity among the synthesized new molecules 12a–k, with an IC50 50 value of 2.82 ± 0.10 μM. Besides, another compound 12a also displayed impressive cytotoxicity against A549 cell line (IC50: 3.00 ± 1.40 μM). Further target-based assay of these two compounds 12c and 12a revealed their potential as DNA intercalative topoisomerase-IIα inhibitors. Additionally, the antiproliferative activity of compound 12c was measured in A549 cells by traditional apoptosis assays revealing the nuclear, morphological alterations, and depolarization of membrane potential in mitochondria and externalization of phosphatidylserine in a concentration-dependent manner. Cell cycle analysis unveiled the G0/G1 phase inhibition and wound healing assay inferred the inhibition of in vitro cell migration by compound 12c in lung cancer cells. Remarkably, the safety profile of compound 12c was disclosed by screening against normal human lung epithelial cell line (BEAS-2B: IC50: 71.2 ± 7.95 μM) with a selectivity index range of 14.9–25.26. Moreover, Molecular modeling studies affirm the intercalative binding of compound 12c and 12a in the active pocket of topo-IIα. Furthermore, in silico prediction of physico-chemical parameters divulged the propitious drug-like properties of the synthesized derivatives.
- Tokala, Ramya,Sana, Sravani,Lakshmi, Uppu Jaya,Sankarana, Prasanthi,Sigalapalli, Dilep Kumar,Gadewal, Nikhil,Kode, Jyoti,Shankaraiah, Nagula
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- Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis
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Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+
- Arnhof, Heribert,Bader, Gerd,Bruchhaus, Jens,Burkard, Michelle,Ciftci, Tuncay,Dahmann, Georg,Du, Alicia,Ettmayer, Peter,Fett, Thomas N.,Garavel, Géraldine,Gerstberger, Thomas,Haering, Daniela,Harrer, Christoph,Hofbauer, Karin S.,Kessler, Dirk,Kousek, Roland,Li, Dongyang,Li, Yali,Lv, Xiaobing,Martinelli, Paola,Mayer, Moriz,McConnell, Darryl B.,Mischerikow, Nikolai,Mitzner, Sophie,Pearson, Mark,Peric-Simov, Biljana,Quant, Jens,Rinnenthal, Joerg,Rumpel, Klaus,Savarese, Fabio,Scherbantin, Yvonne,Schnitzer, Renate,Scholz, Guido,Schrenk, Andreas,Sharps, Bernadette,Sommergruber, Wolfgang,Treu, Matthias,Weinstabl, Harald,Wolkerstorfer, Bernhard,Zahn, Stephan K.,Zhang, Xuechun,Zoephel, Andreas
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supporting information
(2019/09/06)
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- Asymmetric Nazarov Cyclizations Catalyzed by Chiral-at-Metal Complexes
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The application of Lewis acidic chiral-at-metal complexes of iridium(III) and rhodium(III) as catalysts for the asymmetric polarized Nazarov cyclization of dihydropyran- and indole-functionalized α-unsaturated β-ketoesters is reported (overall 24 examples). For both substrate classes, catalyst loadings of 2 mol% were found to be sufficient for achieving high yields and high stereoselectivities. The cyclized dihydropyran products were isolated in 85–98% yield, with 89%–>99% ee, and trans/cis ratios of 15:1–50:1 (9 examples). The cyclized indole products were typically isolated in more than 70% yield and in up to 93% yield, typically with more than 90% ee and in up to 97% ee, and trans/cis ratios of 12:1–28:1 (15 examples). (Figure presented.).
- Mietke, Thomas,Cruchter, Thomas,Larionov, Vladimir A.,Faber, Tabea,Harms, Klaus,Meggers, Eric
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supporting information
p. 2093 - 2100
(2018/04/19)
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- A biocatalytic method for the chemoselective aerobic oxidation of aldehydes to carboxylic acids
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Herein, we present a study on the oxidation of aldehydes to carboxylic acids using three recombinant aldehyde dehydrogenases (ALDHs). The ALDHs were used in purified form with a nicotinamide oxidase (NOx), which recycles the catalytic NAD+ at the expense of dioxygen (air at atmospheric pressure). The reaction was studied also with lyophilised whole cell as well as resting cell biocatalysts for more convenient practical application. The optimised biocatalytic oxidation runs in phosphate buffer at pH 8.5 and at 40 °C. From a set of sixty-one aliphatic, aryl-Aliphatic, benzylic, hetero-Aromatic and bicyclic aldehydes, fifty were converted with elevated yield (up to >99%). The exceptions were a few ortho-substituted benzaldehydes, bicyclic heteroaromatic aldehydes and 2-phenylpropanal. In all cases, the expected carboxylic acid was shown to be the only product (>99% chemoselectivity). Other oxidisable functionalities within the same molecule (e.g. hydroxyl, alkene, and heteroaromatic nitrogen or sulphur atoms) remained untouched. The reaction was scaled for the oxidation of 5-(hydroxymethyl)furfural (2 g), a bio-based starting material, to afford 5-(hydroxymethyl)furoic acid in 61% isolated yield. The new biocatalytic method avoids the use of toxic or unsafe oxidants, strong acids or bases, or undesired solvents. It shows applicability across a wide range of substrates, and retains perfect chemoselectivity. Alternative oxidisable groups were not converted, and other classical side-reactions (e.g. halogenation of unsaturated functionalities, Dakin-Type oxidation) did not occur. In comparison to other established enzymatic methods such as the use of oxidases (where the concomitant oxidation of alcohols and aldehydes is common), ALDHs offer greatly improved selectivity.
- Knaus, Tanja,Tseliou, Vasilis,Humphreys, Luke D.,Scrutton, Nigel S.,Mutti, Francesco G.
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supporting information
p. 3931 - 3943
(2018/09/11)
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- Ring-Opening Diarylation of Siloxydifluorocyclopropanes by Ag(I) Catalysis: Stereoselective Construction of 2-Fluoroallylic Scaffold
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A silver-catalyzed, defluorination ring-opening diarylation of siloxy 2,2-difluorocyclopropanes, with two arenes, to directly prepare polysubstituted 2-fluoroallylic compounds, is described. This multicomponent reaction proceeds smoothly in good stereoselectivity, which is due to a chelation-controlled addition of arenes to α-fluorinated ketone intermediate.
- Song, Xiaoning,Xu, Cong,Du, Dongxu,Zhao, Ziming,Zhu, Dongsheng,Wang, Mang
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supporting information
p. 6542 - 6545
(2017/12/26)
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- Visible-Light-Promoted Oxidative [4 + 2] Cycloadditions of Aryl Silyl Enol Ethers
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Visible-light-promoted oxidative [4 + 2] cycloadditions of μ,3-unsaturated silyl enol ethers have been developed to efficiently and diastereoselectively construct polycyclic skeletons under mild conditions. The diastereoselectivities were dependent on the stereoconfiguration of silyl enol ether, substitutions on the link, as well as electric properties of substitutions on aryl rings. The intermediates could be trapped by TEMPO, oxygen or methanol. Mechanistic studies indicated the reaction was initiated by one-electron oxidation of the silyl enol ether.
- Yang, Bo,Lu, Zhan
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p. 7288 - 7300
(2016/08/30)
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- Chemoselective dehydrogenative esterification of aldehydes and alcohols with a dimeric rhodium(II) catalyst
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Dehydrogenative cross-coupling of aldehydes with alcohols as well as dehydrogentive cross-coupling of primary alcohols to produce esters have been developed using a Rh-terpyridine catalyst. The catalyst demonstrates broad substrate scope and good functional group tolerance, affording esters highly selectively. The high chemoselectivity of the catalyst stems from its preference for dehydrogenation of benzylic alcohols over aliphatic ones. Preliminary mechanistic studies suggest that the active catalyst is a dimeric Rh(ii) species, operating via a mechanism involving metal-base-metal cooperativity.
- Cheng, Junjie,Zhu, Meijuan,Wang, Chao,Li, Junjun,Jiang, Xue,Wei, Yawen,Tang, Weijun,Xue, Dong,Xiao, Jianliang
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p. 4428 - 4434
(2016/07/07)
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- Aerobic Copper-Catalyzed O-Methylation with Methylboronic Acid
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The oxidative coupling of alkylboronic acids with oxygen nucleophiles offers a strategy for replacing toxic, electrophilic alkylating reagents. Although the Chan-Lam reaction has been widely applied in the arylation of heteroatom nucleophiles, O-alkylation with boronic acids is rare. We report a Cu-catalyzed nondecarboxylative methylation of carboxylic acids with methylboronic acid that proceeds in air with no additional oxidant. An isotope-labeling study supports an oxidative cross-coupling mechanism, in analogy to that proposed for Chan-Lam arylation.
- Jacobson, Clare E.,Martinez-Mu?oz, Noelia,Gorin, David J.
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p. 7305 - 7310
(2015/07/28)
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- Direct carboxylation of simple arenes with CO2 through a rhodium-catalyzed C-H bond activation
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Direct carboxylation of simple arenes under atmospheric pressure of CO2 is achieved through a rhodium-catalyzed C-H bond activation without the assistance of a directing group. Various arenes such as benzene, toluene, xylene, electron-rich or electron-deficient benzene derivatives, and heteroaromatics are directly carboxylated with high TONs. This journal is
- Suga, Takuya,Mizuno, Hajime,Takaya, Jun,Iwasawa, Nobuharu
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supporting information
p. 14360 - 14363
(2015/02/19)
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- KAHA ligations that form aspartyl aldehyde residues as synthetic handles for protein modification and purification
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Aldehydes are widely recognized as valuable synthetic handles for the chemoselective manipulation of peptides and proteins. In this report, we show that peptides and small proteins containing the aspartic acid semialdehyde (Asa) side chain can be easily p
- Murar, Claudia E.,Thuaud, Frdric,Bode, Jeffrey W.
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supporting information
p. 18140 - 18148
(2015/03/04)
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- Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors
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Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC50 values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results.
- Dolusic, Eduard,Larrieu, Pierre,Blanc, Sebastien,Sapunaric, Frederic,Norberg, Bernadette,Moineaux, Laurence,Colette, Delphine,Stroobant, Vincent,Pilotte, Luc,Colau, Didier,Ferain, Thierry,Fraser, Graeme,Galeni, Moreno,Frre, Jean-Marie,Masereel, Bernard,Van Den Eynde, Benoit,Wouters, Johan,Frederick, Raphael
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experimental part
p. 1550 - 1561
(2011/03/22)
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- Synthesis of carbazoles by gold(I)-catalyzed carbocyclization of 2-(enynyl)indoles
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A new synthetic protocol for carbazoles through gold(I)-catalyzed intramolecular hydroarylation of (Z)-2-(enynyl)indoles was achieved in good yields. The requisite (Z)-2-(enynyl)indoles were synthesized stereoselectively by trimethylgallium-promoted, Z-selective Wittig olefination of N-alkylindole-2-carboxaldehydes with propargyl ylides. Substrates possessing both alkyl as well as aromatic groups are well tolerated under these reaction conditions. Georg Thieme Verlag Stuttgart.
- Praveen, Chandrasekaran,Perumal, Paramasivan Thirumalai
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scheme or table
p. 521 - 524
(2011/04/17)
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- Direct functionalization of indoles: Copper-catalyzed malonyl carbenoid insertions
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Indoles, when treated with dimethyl diazomalonate under catalysis by Cu(acac)2, undergo C-H insertion reactions regioselectively depending on the substitution pattern on the indole moiety. Indoles where the 3-position is substituted give high yields of the C2-H insertion product. Microwave conditions are also disclosed which show comparable yields with reduced reaction times.
- Johansen, Michael B.,Kerr, Michael A.
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supporting information; experimental part
p. 4956 - 4959
(2010/12/25)
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- Enantioselective organocatalytic intramolecular ring-closing Friedel-Crafts-type alkylation of indoles
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An enantioselective organocatalytic intramolecular ring-closing Friedel-Crafts-type alkylation of indolyl α,β-unsaturated aldehydes has been developed. This powerful new strategy allows enantioselective access to THPIs and THBCs in a straightforward and a
- Li, Chang-Feng,Liu, Hiu,Liao, Jie,Cao, Yi-Ju,Liu, Xiao-Peng,Xiao, Wen-Jing
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p. 1847 - 1850
(2008/02/02)
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- Ramoplanin derivatives possessing antibacterial activity
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Novel ramoplanin derivatives are disclosed. These ramoplanin derivatives exhibit antibacterial activity. As the compounds of the subject invention exhibit potent activities against gram positive bacteria, they are useful antimicrobial agents. Methods of synthesis and of use of the compounds are also disclosed.
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Page/Page column 70-71
(2010/11/23)
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- A domino amidation route to indolines and indoles: Rapid syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine
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(Chemical Equation Presented) When subjected to palladium-catalyzed amidation conditions, 2-triflyloxy phenethyl carbonates undergo, in addition to the expected aryl cross-coupling, an additional amidation with net displacement of the carbonate. The result is a one-step synthesis of indolines which may be oxidized to indoles. The utility of the procedure is illustrated by the two- or three-step syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine.
- Ganton, Michael D.,Kerr, Michael A.
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p. 4777 - 4779
(2007/10/03)
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- N-alkylation of indole derivatives
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The present invention provides methods for the efficient preparation of indole derivatives of the formula wherein X is methyl or benzyl; and R1, R2, R3 and R4 are independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl, alkoxy, aralkoxy, carboxy, alkoxycarbonyl, aryl or heteroaryl; or R1 and R2 combined together with the carbon atoms to which they are attached form a fused 6-membered aromatic ring; by reacting indoles of the formula wherein R1, R2, R3 and R4 have meanings as defined for formula I, with dimethyl carbonate when X is methyl, or with dibenzyl carbonate when X is benzyl, in the presence of a catalytic amount of a base at an ambient temperature to afford compounds of formula I wherein X, R1, R2, R3 and R4 have meanings as defined herein above. In particular, the present invention provides methylation and benzylation of the indole nitrogen in nearly quantitative yields using 1,4-diazabicyclo[2.2.2]octane as the base in a catalytic amount under mild conditions, wherein the alkylations may be conducted in the absence or the presence of an ionic liquid, under microwave irradiation or utilizing conventional heat, or combinations thereof.
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- Design and synthesis of novel indole β-diketo acid derivatives as HIV-1 integrase inhibitors
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Diketo acids such as S-1360 (1A) and L-731,988 (2) are potent and selective inhibitors of HIV-1 integrase (IN). A plethora of diketo acid-containing compounds have been claimed in patent literature without disclosing much biological activities and synthetic details (reviewed in Neamati, N. Exp. Opin. Ther. Pat. 2002, 12, 709-724). To establish a coherent structure - activity relationship among the substituted indole nucleus bearing a β-diketo acid moiety, a series of substituted indole-β-diketo acids (4a-f and 5a-e) were synthesized. All compounds tested showed anti-IN activity at low micromolar concentrations with varied selectivity against the strand transfer process. Three compounds, the indole-3-β-diketo acids 5a and 5c, and the parent ester 9c, have shown an antiviral activity in cell-based assays. We further confirmed a keto-enolic structure in the 2,3-position of the diketo acid moiety of a representative compound (4c) using NMR and X-ray crystallographic analysis. Using this structure as a lead for all of our computational studies, we found that the title compounds extensively interact with the essential amino acids on the active site of IN.
- Sechi, Mario,Derudas, Massimiliano,Dallocchio, Roberto,Dessì, Alessandro,Bacchi, Alessia,Sannia, Luciano,Carta, Fabrizio,Palomba, Michele,Ragab, Omar,Chan, Carney,Shoemaker, Robert,Sei, Shizuko,Dayam, Raveendra,Neamati, Nouri
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p. 5298 - 5310
(2007/10/03)
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- Dual nucleophilic catalysis with DABCO for the N-methylation of indoles
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DABCO is an extremely active catalyst for the methylation of indoles in conjunction with dimethyl carbonate (DMC). This green chemistry is highly effective and produces N-methylindoles in nearly quantitative yields. The reaction sequence consists of competing alkylation and acylation pathways and involves 1,4-diazabicyclo[2.2.2]octane (DABCO) dually as a nucleophilic catalyst, ultimately resulting in a single product: the N-methylated indole.
- Shieh, Wen-Chung,Dell, Steven,Bach, Andrew,Repic, Oljan,Blacklock, Thomas J.
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p. 1954 - 1957
(2007/10/03)
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- New versatile route to the synthesis of tetrahydro-β-carbolines and tetrahydro-pyrano[3,4-b]indoles via an intramolecular Michael addition catalyzed by InBr3
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A simple multistep synthetic strategy to 4-sub-stituted 1,2,3,4-tetrahydro-β-carboline and 1,3,4,9-tetrahydro-pyrano[3,4-b]indole derivatives starting from commercially available indole 2-carboxylic acid (5) is described. The final intramolecular Michael addition promoted by catalytic amount of InBr3 (5-10 mol %) provided the expected polycyclic compounds in excellent yields (up to 97%) both in anhydrous organic and aqueous media.
- Agnusdei, Marianna,Bandini, Marco,Melloni, Alfonso,Umani-Ronchi, Achille
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p. 7126 - 7129
(2007/10/03)
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- Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors
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A series of N-(aminoiminomethyl)-1H-indole carboxamide derivatives were synthesized and their inhibitory potencies against the Na+/H+ exchanger were measured. Variation of the carbonylguanidine group at the 2- to 7- position of the indole ring system showed that a substitution at the 2- position improved the Na+/H+ exchanger inhibitory activity the most in vitro. This led to the synthesis and evaluation of an extensive series of N- (aminoiminomethyl)-1H-indole-2-carboxamide derivatives. Derivatives having an alkyl or substituted alkyl group at the 1-position of the indole ring system showed higher levels of in vitro activities. N-(aminoiminomethyl)-1-(2- phenylethyl)-1H-indole-2-carboxamide (49) had the strongest activity.
- Kitano, Masafumi,Kojima, Atsuyuki,Nakano, Kazuhiro,Miyagishi, Akira,Noguchi, Tsuyoshi,Ohashi, Naohito
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p. 1538 - 1548
(2007/10/03)
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- Heterocyclic compounds having anti-diabetic activity and their use
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Compounds of formula (I): STR1 [wherein: X represents an unsubstituted or substituted indolyl, indolinyl, azaindolyl, azaindolinyl, imidazopyridyl or imidazopyrimidinyl group; Y represents an oxygen or sulfur atom; Z represents a 2,4-dioxothiazolidin-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 3,5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group; R represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a hydroxy group, a nitro group, an aralkyl group or a unsubstituted or substituted amino group; and m is an integer of from 1 to 5] have hypoglycemic and anti-diabetic activities.
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- Benzimidazole-type glycine antagonists: The role of the ring nitrogen atoms
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Several derivatives of 1H-benzimidazole-2-carboxylic acid (BICA, 2a) were tested in vitro in comparison to 1H-indole-2-carboxylic acid (ICA, 1e) for their ability to displace [3H]glycine from rat hippocampal membranes. Compound 2a was 8 times m
- Berger, Michael L.,Scho?dl, Clemens,Noe, Christian R.
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p. 121 - 124
(2007/10/03)
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