- Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex i
-
Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects of mubritinib on cardiac cells showed that this drug did not inhibit HER2 as reported, but directly inhibits mitochondrial respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure resulting in cell death. We used a library of chemical variants of mubritinib and showed that modifying the 1H-1,2,3-triazole altered complex I inhibition, identifying the heterocyclic 1,3-nitrogen motif as the toxicophore. The same toxicophore is present in a second anti-cancer therapeutic carboxyamidotriazole (CAI) and we demonstrate that CAI also functions through complex I inhibition, mediated by the toxicophore. Complex I inhibition is directly linked to anti-cancer cell activity, with toxicophore modification ablating the desired effects of these compounds on cancer cell proliferation and apoptosis.
- Allen, Timothy E. H.,Chung, Injae,Fischer, Peter,Hardy, Rachel,Harvey, Robert F.,Hirst, Judy,Kellam, Barrie,Macfarlane, Marion,Mistry, Sarah,Pryde, Kenneth R.,Serreli, Riccardo,Stephenson, Zo? A.,Stoneley, Mark,Willis, Anne E.
-
-
- Mizoroki–Heck Cross-Coupling of Acrylate Derivatives with Aryl Halides Catalyzed by Palladate Pre-Catalysts
-
The Mizoroki–Heck (MH) reaction involving aryl halides with various acrylates and acrylamides has been studied using air and moisture-stable imidazolium-based palladate pre-catalysts. These pre-catalysts can be converted into Pd-NHC species (NHC = N-heterocyclic carbene) under catalytic conditions and are capable of facilitating the Mizoroki–Heck reaction of aryl halides with various acrylates. The effects of solvent, catalyst loading, temperature and bases on the reaction outcome have been investigated. Various coupling partners were tolerated under the optimal reaction conditions catalyzed by palladate 1, [SIPr·H][Pd(η3-2-Me-allyl)Cl2]. The efficiency of the optimized synthetic methodology was tested on various aryl halides and substituted acrylates as well as acrylamides. The MH reaction yielded the coupled products in good to excellent isolated yields (up to 98%).
- Islam, Mohammad Shahidul,Nahra, Fady,Tzouras, Nikolaos V.,Barakat, Assem,Cazin, Catherine S. J,Nolan, Steven P.,Al-Majid, Abdullah Mohammed
-
supporting information
p. 4695 - 4699
(2019/11/13)
-
- Direct and facile synthesis of primary amides from carboxylic acids via acyl isocyanate intermediates using mukaiyama reagent
-
A very simple and efficient procedure for the preparation of primary amides is described from carboxylic acids using Mukaiyama reagent/KNCO in aqueous acetonitrile. Availability of the reagents, simplicity, and easy workup of the reaction crude make this method attractive for organic chemists.
- Azadi, Roya,Motamedpoor, Zahra
-
p. 801 - 804
(2018/09/26)
-
- Development and Utilization of a Palladium-Catalyzed Dehydration of Primary Amides to Form Nitriles
-
A palladium(II) catalyst, in the presence of Selectfluor, enables the efficient and chemoselective transformation of primary amides into nitriles. The amides can be attached to aromatic rings, heteroaromatic rings, or aliphatic side chains, and the reactions tolerate steric bulk and electronic modification. Dehydration of a peptaibol containing three glutamine groups afforded structure-activity relationships for each glutamine residue. Thus, this dehydration can act similarly to an alanine scan for glutamines via synthetic mutation.
- Al-Huniti, Mohammed H.,Rivera-Chávez, José,Colón, Katsuya L.,Stanley, Jarrod L.,Burdette, Joanna E.,Pearce, Cedric J.,Oberlies, Nicholas H.,Croatt, Mitchell P.
-
supporting information
p. 6046 - 6050
(2018/09/27)
-
- Selective and facile synthesis of α,β-unsaturated nitriles and amides with N-hydroxyphthalimide as the nitrogen source
-
The direct conversion of α,β-unsaturated aldehydes to corresponding nitriles promoted by Pd(OAc)2 and phthalic acid which was hydrolyzed from N-hydroxyphthalimide (NHPI) has been disclosed. Additionally, it was found that when water was used as the solvent, α,β-unsaturated amides was obtained as the main products in good to excellent yields. It was first reported that NHPI was utilized as the nitrogen source to synthesize α,β-unsaturated nitriles and amides from aldehydes. Control experiment demonstrated that aldehydes undergo a process of oximation and dehydration to form nitriles and amides.
- Yan, Yiyan,Xu, Xiaohe,Jie, Xiaokang,Cheng, Jingya,Bai, Renren,Shuai, Qi,Xie, Yuanyuan
-
supporting information
p. 2793 - 2796
(2018/06/25)
-
- Amidation of carboxylic acids via the mixed carbonic carboxylic anhydrides and its application to synthesis of antidepressant (1S,2R)-tranylcypromine
-
Primary amidations of carboxylic acids 1 or 3 with NH4Cl in the presence of ClCO2Et and Et3N were developed to afford the corresponding primary amides in 22% to quantitative yields. Additionally, we have applied the amidation to the preparation of various amides containing hydroxamic acids and achieved the synthesis of (1S,2R)-tranylcypromine as an antidepressant medicine via Lossen rearrangement.
- Ezawa, Tetsuya,Kawashima, Yuya,Noguchi, Takuya,Jung, Seunghee,Imai, Nobuyuki
-
p. 1690 - 1699
(2017/11/14)
-
- Substituted 4-oxo-crotonic acid derivatives as a new class of protein kinase B (PknB) inhibitors: synthesis and SAR study
-
Protein kinase B (PknB) is an essential serine/threonine protein kinase required for Mycobacterium tuberculosis (M. tb) cell division and cell-wall biosynthesis. A high throughput screen using PknB identified a (E)-4-oxo-crotonic acid inhibitor, named YH-8, which was used as a scaffold for SAR investigations. A significant improvement in enzyme affinity was achieved. The results indicated that the α,β-unsaturated ketone scaffold and “trans-” configuration are essential for the activity against PknB. And compounds with an aryl group, especially with electron-withdrawing substituents on benzene ring, exhibited four fold potency than that of YH-8.
- Xu, Changliang,Bai, Xiaoguang,Xu, Jian,Ren, Jinfeng,Xing, Yun,Li, Ziqiang,Wang, Juxian,Shi, Jingjing,Yu, Liyan,Wang, Yucheng
-
p. 4763 - 4775
(2017/02/05)
-
- Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
-
This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.
- Russo, Francesco,Gising, Johan,?kerbladh, Linda,Roos, Annette K.,Naworyta, Agata,Mowbray, Sherry L.,Sokolowski, Anders,Henderson, Ian,Alling, Torey,Bailey, Mai A.,Files, Megan,Parish, Tanya,Karlén, Anders,Larhed, Mats
-
p. 342 - 362
(2015/06/30)
-
- METHOD FOR PRODUCING 4-METHOXY CINNAMIC ACID 2-ETHYLHEXYL COMPOUND
-
PROBLEM TO BE SOLVED: To provide a method for producing a 4-methoxy cinnamic acid 2-ethylhexyl compound friendly for the environment under mild conditions using an inexpensive reagent. SOLUTION: A 4-methoxy cinnamic acid 2-ethylhexyl compound is obtained through: a first step in which a 4-hydroxy cinnamic acid amide compound is treated with a methylation agent to obtain a 4-methoxy cinnamic acid amide compound; a second step in which the 4-methoxy cinnamic acid amide compound is hydrolyzed with acid or a base to obtain a 4-methoxy cinnamic acid compound; and a third step in which the 4-methoxy cinnamic acid compound and the 2-ethyl-1-hexanol are condensed to form an ester linkage. COPYRIGHT: (C)2015,JPOandINPIT
- -
-
Paragraph 0071
(2016/12/22)
-
- Convenient preparation of primary amides via activation of carboxylic acids with ethyl chloroformate and triethylamine under mild conditions
-
Primary amides were easily prepared in 22-99% yields from the corresponding carboxylic acids 1 or 5 with NH4Cl via activation with ClCO 2Et and Et3N. The enantiomers of the corresponding primary amides of Cbz-, Boc-, or Fmoc-α-amino acids can be separated by using a chiral column.
- Noguchi, Takuya,Sekine, Masahiro,Yokoo, Yuki,Jung, Seunghee,Imai, Nobuyuki
-
p. 580 - 582
(2013/07/05)
-
- Heck arylation of conjugated alkenes with aryl bromides or chlorides catalyzed by immobilization of palladium in MCM-41
-
A new 3-(2-aminoethylamino)propyl-functionalized MCM-41-immobilized palladium(II) complex [MCM-41-2N-PdCl2] was conveniently synthesized from commercially available and cheap 3-(2-aminoethylamino) propyltrimethoxysilane via immobilization on MCM-41, followed by reacting with palladium chloride. It was found that this heterogeneous palladium complex is a highly efficient catalyst for Heck arylation of conjugated alkenes with aryl bromides or chlorides using tetrabutylammonium bromide as additive and can be reused for at least six consecutive trials without any decreases in activity.
- Yao, Fang,Liu, Jiaqin,Cai, Mingzhong
-
p. 681 - 686
(2013/07/26)
-
- Ruthenium-catalyzed one-pot synthesis of primary amides from aldehydes in water
-
The readily available arene-ruthenium(ii) complex [RuCl2(η 6-C6Me6){P(NMe2)3}] (5 mol%) proved to be an efficient catalyst for the direct synthesis of primary amides from aldehydes and hydroxylamine hydrochloride (NH2OH· HCl) in water at 100 °C. The process, which requires the presence of NaHCO3 to catch the HCl released during the formation of the key aldoxime intermediates, was operative with both aromatic, heteroaromatic, α,β-unsaturated and aliphatic aldehydes, and tolerated several functional groups. A greener approach using commercially available NH 2OH solution (50 wt.% in water) is also presented.
- Garcia-Alvarez, Rocio,Diaz-Alvarez, Alba E.,Crochet, Pascale,Cadierno, Victorio
-
p. 5889 - 5894
(2013/05/09)
-
- Ruthenium-catalyzed rearrangement of aldoximes to primary amides in water
-
The rearrangement of aldoximes to primary amides has been studied using the readily available arene-ruthenium(II) complex [RuCl2(η 6-C6Me6){P(NMe2)3}] (5 mol %) as catalyst. Reactions proceeded cleanly in pure water at 100 °C without the assistance of any cocatalyst, affording the desired amides in high yields (70-90%) after short reaction times (1-7 h). The process was operative with both aromatic, heteroaromatic, α,β-unsaturated, and aliphatic aldoximes and tolerated several functional groups. Reaction profiles and experiments using 18O-labeled water indicate that two different mechanisms are implicated in these transformations. In both of them, nitrile intermediates are initially formed by dehydration of the aldoximes. These intermediates are then hydrated to the corresponding amides by the action of a second molecule of aldoxime or water. A kinetic analysis of the rearrangement of benzaldoxime to benzamide is also discussed.
- Garcia-Alvarez, Rocio,Diaz-Alvarez, Alba E.,Borge, Javier,Crochet, Pascale,Cadierno, Victorio
-
p. 6482 - 6490
(2012/10/30)
-
- Heck-Matsuda reactions catalyzed by a hydroxyalkyl-functionalized NHC and palladium acetate
-
The functionalized NHC obtained from salt 2 is a good ligand for palladium in the Heck-Matsuda reaction of arenediazonium salts and different alkenes. The reaction is performed with low catalyst loading (0.5-1 mol-% of Pd) and in the absence of a base for acrylates. The protocol is also useful for the preparation of cinnamide derivatives. Compound U-77863 has been prepared successfully in good isolated yield. Cyclohexene was found to be an appropriate substrate for the reaction, giving the corresponding 1-arylcyclohexene as a single regioisomer under the studied reaction conditions. The optimal parameters of the reaction were studied by employing a design of experiments approach. Thus, the use of a small set of reactions allows the trends of the different factors to be studied. This study revealed that the best catalytic system is formed by combination of Pd(OAc)2 and salt 2 in a 1:2 ratio. This catalytic system produces better results without the use of a base. Copyright
- Penafiel, Itziar,Pastor, Isidro M.,Yus, Miguel
-
supporting information; experimental part
p. 3151 - 3156
(2012/07/03)
-
- Binaphthyl-bridged bis-imidazolinium salts as N-heterocyclic carbene ligand precursors in the palladium-catalyzed Heck reaction
-
Two new bis-imidazolinium salts (4a, 4b) have been synthesized as precursors of N-heterocyclic carbenes (NHCs) from the commercially available (R)-2,2′-dihydroxy-1,1′-binaphthalene. The two bis-imidazolinium salts were used as efficient precursor of NHC ancillary ligands in the palladium-catalyzed Heck reaction. Good to excellent yields and high stereoselectivities were obtained with ethyl acrylate, acrylonitrile, and acrylamide as starting materials. The structure of bis-imidazolinium salt 4b was further characterized by single crystal X-ray diffraction analysis. Science China Press and Springer-Verlag Berlin Heidelberg 2011.
- Wu, Hui,Jin, Can,Huang, Guoli,Wang, Lianjun,Jiang, Juli,Wang, Leyong
-
experimental part
p. 951 - 956
(2012/02/05)
-
- Synthesis of substituted styrenes and stilbenes mediated by palladium on zirconia
-
Palladium on zirconia has been found to be an effective catalyst for the synthesis of various substituted styrenes and stilbenes, including biologically active natural products, by reaction of aryl halides with olefins.
- Borate, Hanumant B.,Dumbre, Deepa K.,Wakharkar, Radhika D.,Choudhary, Vasant R.
-
experimental part
p. 495 - 499
(2009/04/06)
-
- The Heck reaction of β-arylacrylamides: An approach to 4-aryl-2-quinolones
-
The Heck reaction of β-arylacrylamides with aryl iodides afforded the corresponding vinylic substitution products usually in high yields. The nature of β-substituents, aryl iodides and substituents at the nitrogen atom influences the stereochemical outcome. N,N-Dimethyl-β-arylacrylamides gave vinylic substitution products with higher stereoselectivity than the corresponding N-unsubstituted β-arylacrylamides. β-Arylacrylamides containing ortho-substituents led to the formation of only one stereoisomer. The procedure was used to prepare 4-aryl-2-quinolones from β-(obromophenyl) acrylamide through a sequential Heck reaction and copper-catalyzed cyclization process. Georg Thieme Verlag Stuttgart.
- Bernini, Roberta,Cacchi, Sandro,De Salve, Ilse,Fabrizi, Giancarlo
-
p. 2947 - 2952
(2008/02/12)
-
- NOVEL OXAZOLE DERIVATIVES, THEIR MANUFACTURE AND USE AS PHARMACEUTICAL AGENTS
-
Object of the present invention are compounds of the general formla (1), their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and thei
- -
-
-
- A catalytic asymmetric synthesis of chiral glycidic acid derivatives through chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid derivatives
-
A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C2-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.
- Imashiro, Ritsuo,Seki, Masahiko
-
p. 4216 - 4226
(2007/10/03)
-
- Superacidic activation of α,β-unsaturated amides and their electrophilic reactions
-
The electrophilic reactivity of α,β-unsaturated amides towards weak nucleophiles such as arenes and cyclohexane, initiated either with triflic acid (CF3SO3H) or with excess AlCl3, has been studied. The amides generally condense readily with aromatics in the presence of AlCl3 to give 3-arylpropionamides and related compounds in excellent yields, while some amides also undergo selective ionic hydrogenation with cyclohexane to give saturated amides. The proposed mechanism of these reactions involves dicationic intermediates (superelectrophiles). The direct observation of a dicationic species (by low-temperature NMR) is reported. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Koltunov, Konstantin Yu.,Walspurger, Stephane,Sommer, Jean
-
p. 4039 - 4047
(2007/10/03)
-
- Rhodium-catalyzed heck-type coupling of boronic acids with activated alkenes in an aqueous emulsion
-
Intermolecular couplings between arylboronic acids and activated alkenes catalyzed by a water-soluble tert-bulyl amphosrhodium complex were found to progress at room temperature and generated Heck-type products with high yields and excellent selectivity. Substitution on the alkene component encouraged the formation of products arising from a conjugate addition-protonation process. In the case of Heck product formation, it was necessary to add two equivalents of the alkene component whereby one equivalent is believed to act as a sacrificial hydride acceptor.
- Lautens, Mark,Mancuso, John,Grover, Harpreet
-
p. 2006 - 2014
(2007/10/03)
-
- Friedel-Crafts alkylation of benzene with α,β-unsaturated amides
-
A variety of α,β-unsaturated amides (RHC=CH 2CONR′2, R=H, Me, Ar; R′=H or Et) readily condense with benzene at room temperature in the presence of an excess of aluminum chloride to give the corresponding 3-phenylpropionamides in excellent yields. This simple, one-pot procedure proved to be efficient and very clean. The mechanism of these and related reactions is discussed and the participation of superelectrophilic dicationic intermediates is suggested.
- Koltunov, Konstantin Yu.,Walspurger, Stéphane,Sommer, Jean
-
p. 3547 - 3549
(2007/10/03)
-
- Heck arylation of conjugated alkenes catalysed by a silica-supported poly-γ-methylselenopropylsiloxane palladium(0) complex, the first polymeric organoselenium palladium complex
-
A silica-supported poly-γ-methylselenopropylsiloxane palladium(O) complex was prepared from poly-γ-chloropropylsiloxane by treatment with sodium methyl-selenolate, followed by reaction with palladium chloride and then reduction with hydrazine hydrate. The first polymeric organoselenium palladium complex is a highly active and stereoselective catalyst for the arylation of conjugated alkenes.
- Cai, Ming-Zhong,Zhou, Jun,Zhao, Hong,Song, Cai-Sheng
-
-
- Palladium-catalysed arylation of butyl acrylate and acrylamide with aryl Iodides in water
-
The Heck arylation of butyl acrylate and acrylamide with aryl iodides in the presence of catalytic amounts of palladium acetate and tetra-n-butylammonium bromide in pure water using potassium carbonate as base gave the corresponding substituted (E)-butyl cinnamates and (E)-cinnamamides in good yields, respectively.
- Zhao, Hong,Cai, Ming-Zhong,Peng, Chun-Yun,Song, Cai-Sheng
-
-
- REACTIONS OF ARYLDIAZONIUM TETRAFLUOROBORATES WITH ACRYLAMIDE IN THE PRESENCE OF THIOCYANATES, BROMIDES, AND CHLORIDES OF ALKALI METALS AND AMMONIUM
-
The reaction of aryldiazonium tetrafluoroborates with acrylamide in a water-acetone mixture (1:2) in the presence of copper or iron salts and additives of thiocyanates (bromides, chlorides) of alkali metals and ammonium yields α-thiocyanato(bromo, chloro)-β-arylpropionamides. These compounds under the action of triethylamine easily eliminate hydrogen thiocyanate (bromide, chloride) with formation of β-arylacrylamides.
- Grishchuk, B. D.,Gorbovoi, P. M.,Kudrik, E. Ya.,Ganushchak, N. I.
-
p. 1620 - 1623
(2007/10/02)
-
- A facile approach to arylacetaldehydes via polymeric palladium catalyst
-
Several arylacetaldehydes 5 were synthesized in moderate yields via Heck reaction of acrylamide (1) with substituted iodobenzenes 2 in the presence of the polymeric catalyst (P)-phenyl-(1,10-phenanthroline)-palladium(0) [(P)-ph-phen·Pd(0)] followed by Hofmann reaction and subsequent hydrolysis.
- Zhuangyu,Yi,Honwen,Tsi-yu
-
p. 539 - 542
(2007/10/02)
-
- A Facile Approach to 2-Arylethylamines via Polymeric Palladium Catalyst
-
2-Arylethylamines were synthesized in moderate yields via Heck reaction of acrylamide with iodobenzenes in the presence of polymeric catalyst P-ph-phen.Pd(0) followed by hydrogenation and subsequent Hofmann reaction.
- Zhuangyu, Zhang,Yi, Pan,Hongwen, Hu,Tsi-yu, Kao
-
p. 3563 - 3574
(2007/10/02)
-
- An interesting chloride ion effect in the Heck reaction
-
Addition of chloride ion is found to enhance the yields of cross-couplings between aryl iodides and selected olefin acceptors.
- Merlic, Craig A.,Semmelhack, M.F.
-
p. C23 - C27
(2007/10/02)
-