- Design, synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors
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The identification of a series of sulfonyl-amino-acetamides as BACE-1 (β-secretase) inhibitors for the treatment of Alzheimer's disease is reported. The derivatives were designed based on the docking simulation study, synthesized and assessed for BACE-1 inhibition in vitro. The designed ligands revealed desired binding interactions with the catalytic aspartate dyad and occupance of S1 and S2′ active site regions. These in silico results correlated well with in vitro activity. Out of 33 compounds synthesized, 12 compounds showed significant inhibition at 10 μM concentration. The most active compound 2.17S had IC50 of 7.90 μM against BACE-1, which was concomitant with results of in silico docking study.
- Jain, Priti,Wadhwa, Pankaj K.,Gunapati, Sinduri,Jadhav, Hemant R.
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- New carboxamide derivatives bearing benzenesulphonamide as a selective COX-II inhibitor: Design, synthesis and structure-activity relationship
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Sixteen new carboxamide derivatives bearing substituted benzenesulphonamide moiety (7a-p) were synthesized by boric acid mediated amidation of appropriate benzenesulphonamide with 2-amino-4-picoline and tested for anti-inflammatory activity. One compound 7c showed more potent anti-inflammatory activity than celecoxib at 3 h in carrageenan-induced rat paw edema bioassay. Compounds 7g and 7k also showed good anti-inflammatory activity comparable to celecoxib. Compound 7c appeared selectivity index (COX-2/COX-1) better than celecoxib. Compound 7k appeared selectivity index (COX-2/COX-1) a little higher than the half of celecoxib while compound 7g is non-selective for COX-2. The LD50 of compounds 7c, 7g and 7k were comparable to celecoxib.
- Ugwu, David Izuchukwu,Okoro, Uchechukwu Chris,Ahmad, Hilal
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- Synthesis, crystal structure and antitumor activity of 1d coordination polymer of ca(ii) and na(i) with n-p-tolylsulfonyl-glycine
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D coordination polymer formed by Ca(II) and Na(I) was synthesized by the reaction of calcium perchlorate, NaOH with N-p-tolylsulfonylglycine in the CH3CH2OH/H2O (v:v = 3:1). It was characterized by elemental analysis, IR and X-ray single crystal diffraction analysis. The crystal of the complex belongs to triclinic, space group P-1 with a = 0.95657(10) nm, b = 1.09171(11) nm, c = 1.8292(2) nm, a = 80.6790(10)°, b = 86.831(2)°, g = 89.957(2)°, V = 1.8821(3) nm3, Z = 2, Dc = 1.599 Mg m-3, μ = 0.507 mm-1, F(000) = 936 and final R1 = 0.0981, wR2 = 0.2262. The complex comprises a seven-coordinated Ca(II) center, with a O7 distorted pengonal coordination environment and a six-coordinated Na(I) center, with distorted octahedron environment. The molecules are connected by the oxygen atoms of carboxylates to form one dimensional chain structure. The antitumor activities against gastric cancer cells of free ligand and its Ca(II) complex were studied by MTT method.
- Tai, Xi-Shi,Li, Fa-Hui
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- Novel Phenoxazinones as potent agonist of PPAR-α: Design, synthesis, molecular docking and in vivo studies
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Background: The use of statin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for the treatment of dyslipidemia has been associated with dose limiting hepatoxicity, mytotoxicity and tolerability due to myalgias thereby necessitating the synthesis of new drug candidates for the treatment of lipid disorder. Methods: The reaction of appropriate benzenesulphonamide with substituted phenoxazinone in the presence of phenylboronic acid gave the targeted compounds. The molecular docking study were carried out using autodock tool against peroxisome proliferator activated receptor alpha. The in vivo lipid profile were assayed using conventional methods. The kidney and liver function test were carried out to assess the effect of the derivatives on the organs. The LD50 of the most active derivatives were determined using mice. Results: The targeted compounds were successfully synthesized in excellent yields and characterized using spectroscopic techniques. The results of the molecular docking experiment showed that they were good stimulant of peroxisome proliferator activated receptor alpha. Compound 9f showed activity at Ki of 2.8 nM and binding energy of 12.6 kcal/mol. All the compounds tested reduced triglyceride, total cholesterol, low density lipoprotein cholesterol and very low density lipoprotein cholesterol level in the mice model. Some of the reported compounds also increased high density lipoprotein cholesterol level in the mice. The compounds did not have appreciable effect on the kidney and liver of the mice used. The LD50 showed that the novel compounds have improved toxicity profile. Conclusion: The synthesis of fifteen new derivatives of carboxamides bearing phenoxazinone and sulphonamide were successful. The compounds possessed comparable activity to gemfibrozil. The reported compounds had better toxicity profile than gemfibrozil and could serve as a replacement for the statins and fibrate class of lipid agents.
- Ugwu, David I.,Okoro, Uchechukwu C.,Mishra, Narendra K.,Okafor, Sunday N.
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- Synthesis, characterization, and biological activity of five new mixed-ligand palladium(II) complexes with ethylenediamine and 4-toluenesulfonyl-L-amino acid dianion
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Five new palladium(II) complexes with 4-toluenesulfonyl-L-amino acid dianion and en, [Pd(en)(TsserNO)] (1), [Pd(en)(TsglyNO)] (2), [Pd(en)(TsalaNO)]·1.5H2O (3), [Pd(en)(TsleuNO)]·H 2O (4), and [Pd(en)(TspheNO)]·2H2O (5), have been synthesized and characterized by elemental analysis, IR, UV, 1H NMR, and mass spectrometry. Crystal structure of 1 has been determined by X-ray diffraction analysis. The cytotoxicity was tested by MTT and SRB assays. The results indicate 1-5 exert cytotoxic effects against HL-60, Bel-7402, BGC-823, and KB cell lines and 5 displays the best cytotoxicity. The structure-activity relationships suggest that both amino acid and N-containing ligands have important effects on cytotoxicity. Copyright
- Zhang, Jinchao,Ma, Lili,Zhang, Fangfang,Zhang, Zhilei,Li, Luwei,Wang, Shuxiang
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- Synthesis, characterization, and cytotoxicity of mixed-ligand complexes of platinum(II) with 2,2′-bipyridine and 4-toluenesulfonyl-L-amino acid dianion
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Five new platinum(II) complexes (1-5) with 4-toluenesulfonyl-L-amino acid dianion and 2,2′-bipyridine (bipy) have been synthesized and characterized by elemental analysis, IR, UV, 1H-NMR, 13C-NMR, and mass spectra. The crystal structure of 1 has been determined by X-ray diffraction analysis. Cytotoxicity was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) and sulforhodamine B (SRB) assays. The results indicate that 1-5 exert cytotoxic effects with selectivity against tested carcinoma cell lines; 5 displays better cytotoxicity against BGC-823, Bel-7402, and KB cell lines, while 1 has better cytotoxicity against KB cell line. The 4-toluenesulfonyl- L-amino acid dianions have important effects on cytotoxicity; when 4-toluenesulfonyl-L-amino acid dianions are 4-toluenesulfonyl-L-glycine and 4-toluenesulfonyl-L-phenylalanine, the complexes show better cytotoxicity.
- Zhang, Jin Chao,Li, Luwei,Ma, Lili,Zhang, Fangfang,Wang, Shuxiang
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- Chiral Br?nsted Acid Catalyzed Enantioselective Dehydrative Nazarov-Type Electrocyclization of Aryl and 2-Thienyl Vinyl Alcohols
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An efficient chiral Br?nsted acid-catalyzed enantioselective dehydrative Nazarov-type electrocyclization (DNE) of electron-rich aryl- and 2-thienyl-β-amino-2-en-1-ols is described. The 4π conrotatory electrocyclization reaction affords access to a wide variety of the corresponding 1H-indenes and 4H-cyclopenta[b]thiophenes in excellent yields of up to 99% and enantiomeric excess (ee) values of up to 99%. Experimental and computational studies based on a proposed intimate contact ion-pair species that is further assisted by hydrogen bonding between the amino group of the substrate cation and chiral catalyst anion provide insight into the observed product enantioselectivities.
- Jin, Jianwen,Zhao, Yichao,Gouranourimi, Ali,Ariafard, Alireza,Hong Chan, Philip Wai
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- Synthesis, characterization, and cytotoxicity of complexes of palladium(II) with 1,4-diaminobutane/1,3-diaminopropane and 4-toluenesulfonyl-L-amino acid dianion
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Eight new palladium(II) complexes with 4-toluenesulfonyl-L-amino acid dianion and 1,4-dab/1,3-dap, [Pd(1,4-dab)(TsglyNO)]H2O (1), [Pd(1,4-dab)(TsvalNO)] (2), [Pd(1,4-dab)(TsleuNO)] (3), [Pd(1,4-dab)(TsileNO)] (4), [Pd(1,4-dab)(TsserNO)]0.5H2O (5), [Pd(1,4-dab)(TspheNO)]0. 5H2O (6), [Pd(1,4-dab)(TsthrNO)]H2O (7), and [Pd(1,3-dap)(TsserNO)] (8), have been synthesized and characterized by elemental analysis, IR, UV, 1H NMR, and mass spectrometry. Crystal structure of 8 has been determined by X-ray diffraction. The cytotoxicities were tested by MTT assay. The results indicate the complexes exert cytotoxic effects against HL-60 and Bel-7402. The structure-activity relationship suggests that both amino acids and N-containing ligands have important effects on cytotoxicity, but the IC50 values do not show definite correlation with variation of these ligands.
- Ma, Lili,Zhang, Jinchao,Zhang, Fangfang,Chen, Chao,Li, Luwei,Wang, Shuxiang,Li, Shenghui
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- β-cyclodextrin-catalyzed monosulfonylation of amines and amino acids in water
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A mild and efficient procedure has been developed for the first time under biomimetic conditions for the monosulfonylation of various amines and amino acids catalyzed by β-cyclodextrin in water at room temperature to afford the corresponding sulfonamides in high yields.
- Sridhar,Srinivas,Kumar, V. Pavan,Narender,Rao, K. Rama
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- Inducing Endoplasmic Reticulum Stress to Expose Immunogens: A DNA Tetrahedron Nanoregulator for Enhanced Immunotherapy
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Immunogenic cell death (ICD) is an important modulation type for stimulating anticancer immune responses and amplifying immunotherapy efficacy. When ICD occurs, endoplasmic reticulum (ER) stress plays a vital role for exposing immunogens. Herein, a functionalized DNA tetrahedron nanoregulator to specifically trigger ER stress for enhancing cancer immunotherapy is designed. The nanoregulator can target ER organelles by binding to the sulfonamide receptor of cancer cells. Then glucose depletion and reactive oxygen species generation cause a strong ER stress response to induce ICD to expose tumor immunogens. Thereafter, the dendritic cell (DC) maturation is promoted, and T cell proliferation and infiltration are stimulated to advance cancer immunotherapy. Combined with immune checkpoint inhibitor (α-PD-1), the ER stress triggered nanoregulator exhibits significant suppression for breast cancer and melanoma.
- Li, Yanhua,Zhang, Xia,Wan, Xiuyan,Liu, Xiaohan,Pan, Wei,Li, Na,Tang, Bo
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- Silver-Catalyzed C(sp3)-H Sulfonylation for the Synthesis of Benzyl Sulfones Using Toluene Derivatives and α-Amino Acid Sulfonamides
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We describe a simple and practical protocol for the synthesis of benzyl sulfones using readily available toluene derivatives and α-amino acid sulfonamides. The reaction proceeds to afford a broad range of benzyl sulfones in moderate to high yields under silver catalysis. The mechanism possibly involves a Minisci-type formation of α-aminoalkyl radical, homolytic cleavage of a N-S bond to generate a sulfonyl radical, and coupling of sulfonyl radical with a benzyl radical formed via hydrogen abstraction by sulfate anion radical. The practicality of the present reaction is demonstrated by a gram-scale synthesis and one-step synthesis of anticancer-active compound. The mechanism studies are conducted using radical scavengers and deuterated toluene.
- Kanyiva, Kyalo Stephen,Shibata, Takanori,Uchida, Kanako
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p. 1377 - 1384
(2021/06/06)
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- IMPROVED PROCESS FOR THE PREPARATION OF ROXADUSTAT
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A synthetic route for the preparation of Roxadustat, or a pharmaceutically acceptable salt thereof. Each route involves several novel intermediates and avoids the use of column chromatography.
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Page/Page column 18; 23
(2021/10/30)
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- Electrochemical synthesis of sulfonamides in a graphite powder macroelectrode
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The electrochemical generation of sulfinyl radicals from commercially available and non-expensive sodium salts of sulfinic acids is described. Electrooxidation reactions were carried out in a graphite powder macroelectrode using an aqueous electrolyte and cavity cell. Further reaction with primary or secondary amines gave the corresponding sulfonamides, a unit present in several biologically active compounds and pharmaceuticals, in good yields.
- Galdino, Danilo,Menezes, Paulo H.,Navarro, Marcelo,Vicente, Dmistocles A.
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supporting information
p. 5262 - 5266
(2020/09/17)
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- Synthesis and Structure-Activity Relationships of Arylsulfonamides as AIMP2-DX2 Inhibitors for the Development of a Novel Anticancer Therapy
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AIMP2-DX2, a splicing variant of AIMP2, is up-regulated in lung cancer, possesses oncogenic activity, and results in tumorigenesis. Specifically inhibiting the interaction between AIMP2-DX2 and HSP70 to suppress AIMP2-DX2-dependent cancers with small molecules is considered a promising avenue for cancer therapeutics. Optimization of hit BC-DXI-04 (IC50 = 40.1 μM) provided new potent sulfonamide based AIMP2-DX2 inhibitors. Among these, BC-DXI-843 showed improved inhibition against AIMP2-DX2 (IC50 = 0.92 μM) with more than 100-fold selectivity over AIMP2 in a luciferase assay. Several binding assays indicated that this compound effectively induces cancer cell apoptosis by specifically interrupting the interaction between DX2 and HSP70, which leads to the degradation of DX2 via Siah1-mediated ubiquitination. More importantly, BC-DXI-843 demonstrated in vivo efficacy in a tumor xenograft mouse model (H460 cells) at a dosage of 50 mg/kg, suggesting it as a promising lead for development of novel therapeutics targeting AIMP2-DX2 in lung cancer.
- Sivaraman, Aneesh,Kim, Dae Gyu,Bhattarai, Deepak,Kim, Minkyoung,Lee, Hwa Young,Lim, Semi,Kong, Jiwon,Goo, Ja-Il,Shim, Seunghwan,Lee, Seungbeom,Suh, Young-Ger,Choi, Yongseok,Kim, Sunghoon,Lee, Kyeong
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p. 5139 - 5158
(2020/05/05)
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- Intramolecular Aminoazidation of Unactivated Terminal Alkenes by Palladium-Catalyzed Reactions with Hydrogen Peroxide as the Oxidant
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The palladium-catalyzed aminoazidation of aminoalkenes yielding azidomethyl-substituted nitrogen-containing heterocycles was developed. The procedure requires oxidative conditions and occurs at room temperature in the presence of hydrogen peroxide and NaN3 as the azide source. These conditions provide selective exo-cyclization/azidation of the carbon-carbon double bond, furnishing a versatile approach toward five-, six-, and seven-membered heterocyclic rings.
- Beccalli, Egle M.,Broggini, Gianluigi,Foschi, Francesca,Lo Presti, Leonardo,Loro, Camilla,Oble, Julie,Poli, Giovanni,Sala, Roberto
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supporting information
(2020/02/28)
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- Synthesis, Characterization, and Reactivity of an Ethynyl Benziodoxolone (EBX)-Acetonitrile Complex
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The synthesis of a crystalline ethynyl-1,2-benziodoxol-3(1H)-one (EBX)-acetonitrile complex is described. EBX has been widely used as an active species for a variety of reactions; however, its high instability has so far prevented its isolation. The EBX-acetonitrile is self-assembled into a double-layered honeycomb structure through weak hypervalent iodine secondary interactions and hydrogen bonding. The N-ethynylation of a variety of sulfonamides using the EBX-acetonitrile complex as a substrate under mild conditions is also described.
- Yudasaka, Masaharu,Shimbo, Daisuke,Maruyama, Toshifumi,Tada, Norihiro,Itoh, Akichika
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supporting information
p. 1098 - 1102
(2019/05/16)
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- Iodine-Catalyzed Synthesis of Chiral 4-Imidazolidinones Using α-Amino Acid Derivatives via Dehydrogenative N-H/C(sp3)-H Coupling
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An efficient method for the asymmetric synthesis of 4-imidazolidinones via an iodine-catalyzed intramolecular N-H/C(sp3)-H activation of readily available and abundant feedstocks, amino acids, and amines is described. The reaction proceeded under visible light irradiation to afford a variety of 4-imidazolidinone derivatives under mild conditions in moderate to excellent yields. Secondary and tertiary C(sp3)-H bonds were aminated, and various functional groups were tolerated.
- Kanyiva, Kyalo Stephen,Tane, Marina,Shibata, Takanori
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p. 12773 - 12783
(2019/09/09)
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- Synthesis, characterization and in vitro antitrypanosomal activities of new carboxamides bearing quinoline moiety
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The reported toxicities of current antitrypanosomal drugs and the emergence of drug resistant trypanosomes underscore the need for the development of new antitrypanosomal agents. We report herein the synthesis and antitrypanosomal activity of 24 new amide derivatives of 3-aminoquinoline, bearing substituted benzenesulphonamide. Nine of the new derivatives showed comparable antitrypanosomal activities at IC50 range of 1–6 nM (melarsoprol 5 nM). Compound 11n and 11v are more promising antitrypanosomal agents with IC50 1.0 nM than the rest of the reported derivatives. The novel compounds showed satisfactory predicted physico-chemical properties including oral bioavailability, permeability and transport properties.
- Ugwu, David Izuchukwu,Okoro, Uchechukwu Chris,Mishra, Narendra Kumar
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- Pd(ii)-Catalyzed aerobic 1,2-difunctionalization of conjugated dienes: Efficient synthesis of morpholines and 2-morpholones
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A novel and efficient methodology concerning the Pd(ii)-catalyzed intermolecular difunctionalization of conjugated dienes is reported to synthesize a series of functionalized morpholines and 2-morpholones. Widely distributed and easily obtained β-amino alcohols and α-amino acids, as starting nitrogen and oxygen sources, are successfully applied in the difunctionalization of conjugated dienes respectively. The majority of the desired products were obtained in moderate to excellent yields. Oxygen was successfully employed as a terminal oxidant. Further transformation of the generated products allowed for the expansion of structural diversity.
- Wen, Ke,Wu, Zhengxing,Chen, Buyun,Chen, Jianzhong,Zhang, Wanbin
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supporting information
p. 5618 - 5625
(2018/08/17)
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- Metal-Free N–H/C–H Coupling for Efficient Asymmetric Synthesis of Chiral Dihydroquinoxalinones from Readily Available α-Amino Acids
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We have developed a method for the synthesis of dihydroquinoxalinones via intramolecular N–H/C–H coupling using hypervalent iodine. The starting materials were prepared from inexpensive and readily available aniline and amino acid derivatives. Various functional groups were tolerated to give multisubstituted dihydroquinoxalinones in moderate to excellent yields. The chirality of the amino acid was transferred to the desired target compound without a loss of enantiomeric excess. Preliminary mechanistic studies indicated that the reaction proceeds via an ionic mechanism.
- Kanyiva, Kyalo Stephen,Horiuchi, Masashi,Shibata, Takanori
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supporting information
p. 1067 - 1070
(2018/03/06)
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- Development of Piperazinediones as dual inhibitor for treatment of Alzheimer's disease
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Novel multifunctional 3,6-Diphenyl-1,4-bis(phenylsulfonyl)piperazine-2,5-dione derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). The designed scaffold has blood brain barrier penetrating ability, acetylcholinesterase (AChE) and matrix metalloproteinase-2 (MMP-2) inhibition potential. Compounds 52 and 46 showed very significant inhibition against AChE, IC50 = 32.45 ± 0.044, 28.65 ± 0.029, BuChE, IC50 = 157.95 ± 0.264, 160.58 ± 0.082 and MMP-2, IC50 = 36.83 ± 0.015, 19.57 ± 0.005 (nM). In the enzyme kinetics study, lead molecule 46 showed non-competitive inhibition of AChE with Ki = 7 nM and competitive inhibition of MMP-2 with Ki = 20 nM. Compounds 52 and 46 inhibited AChE-induced Aβ aggregation at 20 μM. The compounds also exhibited in-vitro antioxidant potential in DPPH assay. Further, compound 46 was found to be a promising neuroprotective agent in MC65 cells. Lead molecule 46 significantly enhanced working memory in scopolamine induced amnesia animal model at dose of 5 mg/kg dose. The mitochondrial membrane potential was restored in animals when treated with compounds 52 and 46.
- Kumar, Devendra,Gupta, Sukesh K.,Ganeshpurkar, Ankit,Gutti, Gopichand,Krishnamurthy, Sairam,Modi, Gyan,Singh, Sushil K.
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- α-Amino Acid Sulfonamides as Versatile Sulfonylation Reagents: Silver-Catalyzed Synthesis of Coumarins and Oxindoles by Radical Cyclization
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We developed a silver-catalyzed strategy for the generation of sulfonyl radicals from sulfonamides derived from α-amino acids. The reaction proceeded via a decarboxylation, N–S bond cleavage and radical cyclization sequence and allows the difunctionalization of alkynes and the synthesis of 3-sulfonylated coumarins. The reaction tolerated a broad scope of substrates and functional groups and could be extended to the synthesis of oxindoles and an isoquinolinedione by the capturing of the sulfonyl radical with an alkene moiety. Moreover, the proposed mechanism was supported experimentally and by DFT calculations.
- Kanyiva, Kyalo Stephen,Hamada, Daisuke,Makino, Sohei,Takano, Hideaki,Shibata, Takanori
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supporting information
p. 5905 - 5909
(2018/09/14)
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- Synthesis, characterization, molecular docking and in?vitro antimalarial properties of new carboxamides bearing sulphonamide
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Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in?vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in?vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08?μM respectively comparable with chloroquine 0.06?μM. Compound 7c was the most potent antioxidant agent with IC50 value of 0.045?mM comparable with 0.34?mM for ascorbic acid. In addition to the successful synthesis of the target molecules using boric acid catalysis, the compounds were found to have antimalarial and antioxidant activities comparable with known antimalarial and antioxidant drugs. The class of compounds reported herein have the potential of reducing oxidative stress arising from malaria parasite and chemotherapeutic agent used in the treatment of malaria.
- Ugwu,Okoro,Ukoha,Okafor,Ibezim,Kumar
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p. 349 - 369
(2017/05/04)
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- Synthesis of Six- and Seven-Membered Chloromethyl-Substituted Heterocycles via Palladium-Catalyzed Amino- and Oxychlorination
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The synthesis of six- and seven-membered chloromethyl-substituted heterocycles, such as piperazinone, tetrahydroquinoxaline, benzodiazepinone, and benzoxazepinone, is reported using palladium-catalyzed vicinal diheterofunctionalization of nonactivated alkenes. The reaction conditions for this domino process are soft and mild, and the chloromethyl appendage allows various post-functionalizations via simple nucleophilic substitutions.
- Manick, Anne-Doriane,Berhal, Farouk,Prestat, Guillaume
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supporting information
p. 3719 - 3729
(2016/11/08)
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- Palladium-Catalyzed Modular Synthesis of Substituted Piperazines and Related Nitrogen Heterocycles
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We report here a novel method for the modular synthesis of highly substituted piperazines and related bis-nitrogen heterocycles via a palladium-catalyzed cyclization reaction. The process couples two of the carbons of a propargyl unit with various diamine components to provide nitrogen heterocycles in generally good to excellent yields and high regio- and stereochemical control. (Chemical Equation Presented).
- Montgomery, Thomas D.,Rawal, Viresh H.
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supporting information
p. 740 - 743
(2016/03/01)
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- Gold-Catalyzed Aminoalkenylation of β-Amino-1,n-Diynols to Cycloalkyl-, Piperidinyl- and Pyranyl-Fused Pyrroles
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A synthetic method to prepare cycloalkyl-, piperidinyl- and pyranyl-fused pyrroles efficiently by gold(I)-catalyzed dehydrative aminoalkenylation of β-amino-1,n-diynols under mild conditions at room temperature is described.
- Kothandaraman, Prasath,Zhao, Yichao,Lee, Bo Ra,Le Ng, Clarrisa Jia,Lee, Jun Yi,Ayers, Benjamin James,Chan, Philip Wai Hong
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supporting information
p. 1385 - 1391
(2016/05/19)
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- Palladium-Catalyzed Mono-Selective ortho C H Arylation of Aryl Sulfonamides in Water: A Concise Access to Biaryl Sulfoamide Derivatives
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A green atom-economical method for the synthesis of biaryl sulfonamide derivatives via palladium(II)-catalyzed C H bond activation by employing an amino acid moiety as the bidentate directing group has been developed. The protocol proceeded efficiently in water; high yields and broad substrate scope were achieved. The reaction shows good functional group compatibility and proceeds in a highly selective manner at the ortho position of arenes connected to sulfonamide sulfur atoms. This auxiliary can be easily removed either by acidic hydrolysis, or converted into primary biaryl sulfomamides with a 30 mol % amount of CuO as catalyst. Mechanistic studies show that the present bidentate directing group is essential for promoting ortho C H bond activation of arenes connected to sulfonamide sulfur atoms. (Figure presented.) .
- Liu, Wei,Wang, Dongyin,Zhao, Yongli,Yi, Fei,Chen, Junmin
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supporting information
p. 1968 - 1974
(2016/07/06)
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- Cu(II)-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids to primary aryl sulfonamides
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A novel protocol for CuO-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids was developed. It is the first example of using an accessible amino acid as an ammonia synthetic equivalent for the synthesis of primary aryl sulfonamides via oxidative decarboxylation/elimination reactions. The present protocol shows excellent functional group tolerance and provides an efficient method for the synthesis of primary aryl sulfonamides in excellent yields.
- Zhou, Liandi,Li, Xiaokang,Liu, Wei,Zhao, Yongli,Chen, Junmin
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supporting information
p. 1299 - 1306
(2016/08/16)
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- Identification of bidentate salicylic acid inhibitors of PTP1B
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PTP1B is a master regulator in the insulin and leptin metabolic pathways. Hyper-activated PTP1B results in insulin resistance and is viewed as a key factor in the onset of type II diabetes and obesity. Moreover, inhibition of PTP1B expression in cancer cells dramatically inhibits cell growth in vitro and in vivo. Herein, we report the computationally guided optimization of a salicylic acid-based PTP1B inhibitor 6, identifying new and more potent bidentate PTP1B inhibitors, such as 20h, which exhibited a > 4-fold improvement in activity. In CHO-IR cells, 20f, 20h, and 20j suppressed PTP1B activity and restored insulin receptor phosphorylation levels. Notably, 20f, which displayed a 5-fold selectivity for PTP1B over the closely related PTPσ protein, showed no inhibition of PTP-LAR, PRL2 A/S, MKPX, or papain. Finally, 20i and 20j displayed nanomolar inhibition of PTPσ, representing interesting lead compounds for further investigation.
- Haftchenary, Sina,Jouk, Andriana O.,Aubry, Isabelle,Lewis, Andrew M.,Landry, Melissa,Ball, Daniel P.,Shouksmith, Andrew E.,Collins, Catherine V.,Tremblay, Michel L.,Gunning, Patrick T.
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p. 982 - 986
(2015/09/22)
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- Carbonic anhydrase inhibitors: Design, synthesis, kinetic, docking and molecular dynamics analysis of novel glycine and phenylalanine sulfonamide derivatives
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The inhibition of two human cytosolic carbonic anhydrase isozymes I and II, with some novel glycine and phenylalanine sulfonamide derivatives were investigated. Newly synthesized compounds G1-4 and P1-4 showed effective inhibition profiles with KI values in the range of 14.66-315 μM for hCA I and of 18.31-143.8 μM against hCA II, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico docking studies were applied. Atomistic molecular dynamic simulations were performed for docking poses which utilize to illustrate the inhibition mechanism of used inhibitors into active site of CAII. These sulfonamide containing compounds generally were competitive inhibitors with 4-nitrophenylacetate as substrate. Some investigated compounds here showed effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide, sulfanilamide or mafenide and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents.
- Fidan, Ismail,Salmas, Ramin Ekhteiari,Arslan, Mehmet,?entürk, Murat,Durdagi, Serdar,Ekinci, Deniz,?entürk, Esra,Co?gun, Sedat,Supuran, Claudiu T.
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p. 7353 - 7358
(2015/11/27)
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- Flow synthesis and biological activity of aryl sulfonamides as selective carbonic anhydrase IX and XII inhibitors
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A series of secondary and tertiary aryl sulfonamides were synthesized under flow conditions and evaluated for their ability to selectively inhibit tumor-associated carbonic anhydrase isoforms IX and XII. The tested compounds revealed to be highly potent CA IX inhibitors in nanomolar range, and to inhibit CA XII activity with different ranks of potencies. Remarkably, 4-methyl-N-phenyl-benzenesulfonamide was a selective nanomolar CA IX inhibitor with an IC50 of 90 nM.
- Rosatelli, Emiliano,Carotti, Andrea,Ceruso, Mariangela,Supuran, Claudiu T.,Gioiello, Antimo
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supporting information
p. 3422 - 3425
(2014/07/22)
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- Building a sulfonamide library by eco-friendly flow synthesis
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A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe, and easily scalable preparation of sulfonamides by use of a meso-reactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media, and nontoxic reactants are achieved by the optimization of the flow setup and experimental protocol designed to sequentially synthesize primary, secondary, and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation.
- Gioiello, Antimo,Rosatelli, Emiliano,Teofrasti, Michela,Filipponi, Paolo,Pellicciari, Roberto
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supporting information
p. 235 - 239
(2013/06/27)
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- Stereoselective synthesis and applications of nitrogen substituted donor-acceptor cyclopropanes (N-DACs) in the divergent synthesis of azacycles
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A new, highly stereoselective intramolecular cyclopropanation of vinylogous carbamates with carbenes in the presence of Cu(acac)2 as the catalyst has been developed for the construction of cyclopropapyrrolidinones. The 'syn' isomer of N-DAC can be converted to the 'anti' isomer by simple silica gel treatment. Regioselective cleavage of each of the cyclopropane bonds of these two acceptor substituted N-DACs led to a diverse array of azacycles.
- Gharpure, Santosh J.,Vijayasree,Reddy, S. Raja Bhushan
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supporting information; scheme or table
p. 1735 - 1738
(2012/04/17)
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- ZnO and ZnO-nanoparticles: Efficient and reusable heterogeneous catalysts for one-pot synthesis of N-acylsulfonamides and sulfonate esters
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Commercially available and preparative ZnO nanoparticles are reported as efficient and reusable catalysts for the chemoselective synthesis of N-acylsulfonamides and sulfonate esters. A one-pot sequential sulfonylation and acylation of amines took place to afford the N-acylsulfonamides in excellent yields under solvent-free conditions. The ZnO catalyst can be reused for without significant loss of catalytic activity.
- Tamaddon, Fatemeh,Sabeti, Mohammad Reza,Jafari, Abbas Ali,Tirgir, Farhang,Keshavarz, Elham
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experimental part
p. 41 - 45
(2012/01/12)
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- CsF-Celite as an efficient heterogeneous catalyst for sulfonylation and desulfonylation of heteroatoms
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CsF-Celite is found to be as an efficient reusable catalyst for sulfonylation and desulfonylation of heteroatoms. Sulfonamides and N-acylsulfonamides deprotect efficiently in the presence of CsF-Celite under solvent free conditions to give the free amines or amides in good to excellent yields.
- Tamaddon, Fatemeh,Nasiri, Alireza,Farokhi, Somayeh
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experimental part
p. 1477 - 1482
(2012/06/18)
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- Cross-enyne and ring-closing metathesis cascade: A building-block approach suitable for diversity-oriented synthesis of densely functionalized macroheterocycles with amino acid scaffolds
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Suitably functionalized glycine derivatives undergo a cross-enyne and ring-closing metathesis cascade to generate macroheterocyclic ring systems in good yield. These macrocycles, prepared on the basis of a fragment coupling strategy, consist of 13-16-membered rings. To this end, 1,5-hexadiene was found to be a promising cross-coupling partner to generate macrocycles by this tandem metathesis sequence. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Kotha, Sambasivarao,Singh, Kuldeep
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p. 5909 - 5916
(2008/04/13)
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- SMALL MOLECULE INHIBITORS OF STAT3 WITH ANTI-TUMOR ACTIVITY
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The present invention concerns compounds, compositions containing these compounds, and methods of using these compounds and compositions as inhibitors of Stat3 signaling, Stat3 dimerization, Stat3-DNA binding, Stat5-DNA binding, and/or aberrant cell growthinvitro or in vivo, e.g., as anti-cancer agents for treatment of cancer, such as breast cancer. The compounds of the invention include, but are not limited to, NSC 74859 (S3I-201), NSC 42067, NSC 59263, NSC 75912, NSC 11421, NSC 91529, NSC 263435, and pharmaceutically acceptable salts and analogs of the foregoing. Other non-malignant diseases characterized by proliferation of cells that may be treated using the compounds of the invention, but are not limited to, cirrhosis of the liver; graft rejection; restenosis; and disorders characterized by a proliferation of T cells such as autoimmune diseases, e.g., type 1 diabetes, lupus and multiple sclerosis. The invention further includes an in-vitro screening test for the presence of malignant cells in a mammalian tissue; a method of identifying inhibitors of constitutive Stat3 activation, Stat3-DNA binding, Stat5-DNA binding, and/or Stat3 dimerization; and a method of identifying anti-cancer agents.
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Page/Page column 66
(2008/06/13)
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- Allylation of aldehydes and imines: Promoted by reuseable polymer-supported sulfonamide of N-glycine
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A allylation of aldehydes and imines (generated in situ from aldehydes and amines) with allyltributyltin promoted by recoverable and reusable the polymer-supported sulfonamide of N-glycine has been developed. Good to high yields were obtained in various cases. Most of the SnBu3 residue can be recovered as Bu3SnCl. Highly stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine 7 was achieved by using the P4a-mediated allylation of Boc-L-phenylglycinal as a key step.
- Li, Gui-Long,Zhao, Gang
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p. 633 - 636
(2007/10/03)
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- Competitive electron transfers from a tyrosyl side-chain and peptide bond in the photodegradation of N-tosyl α-aminomethylamides: An insight into photosynthesis and photodamage in the biological oxidation of water?
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Photo-excited N-tosyl derivatives of phenylalanyl- and, more particularly, O-methyltyrosylmethylamides undergo electron transfer from aryl to tosyl groups whereas the photo-degradation of aliphatic analogues is initiated by electron transfer from the peptide bond, suggesting the latter as one possible reason for the rapid turnover of the D1 protein in biological water oxidation when the essential mediating role of tyrosine 116 in the PSII complex is inhibited.
- Hill, Roger R.,Moore, Sharon A.,Roberts, David R.
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p. 2838 - 2839
(2007/10/03)
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- Juvenile hormone like substances: Part XV - Synthesis and biological activities of some juvenile hormone analogues containing sulphonamide feature
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A large number of juvenile hormone analogues 4-19 containing sulphonamide feature have been synthesized. Preliminary biological screening of one representative, N-(2-oxo-2-piperidino-ethyl) benzenesulphonamide 16a reveals a positive juvenile hormonal activity and chemosterilizing effect against potato tuber moth Phthorimaea operculella.
- Mahajan,Patial, Ved Parkash,Sharma, Pamita
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p. 2635 - 2641
(2007/10/03)
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- Amino acids in the syntheses of heterocyclic systems: Syntheses and radiostability of novel biologically active triazoles containing the sulfonamide moiety
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A number of novel triazoles 2a-f, 4, 9, 10, 12, 15; triazolothiadiazoles 6, 8, 11, 16; triazolothiadizine 5; and triazolotriazine 14 were synthesized and characterized by elemental analyses and spectral data. Six of the compounds showed antifungal activity compared with the fungicide Mycostatine. Radiosterilization of the biologically active compounds 4, 8, 9b, and 10 in the dry state may prove to be applicable at the sterile dose 25 kGy.
- El-Sharief,Ghorab,El-Gaby,Mohamed,Ammar
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p. 316 - 323
(2007/10/03)
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- HIV protease inhibitors based on amino acid derivatives
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A compound selected from the group consisting of a compound of formula I 1a compound of formula II 2and when the compound of formula I and II comprises an amino group pharmaceutically acceptable ammonium salts thereof, wherein R1, R2, Cx, n, R3, R4, R5, Y are as defined in the specification.
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- Synthesis of a [2]benzazepine analogue of clavizepine
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The synthesis of N-tosylbenzopyran[2]benzazepinone 2 using a simple protocol for assembly of an azepine ring on the xanthene skeleton is described. Formation of the C-C bond between C9 of the xanthen-9-ol 7 and the β-C of N-tosyl aminoacetaldehyde dimethyl acetal leads to 10, which upon treatment with formaldehyde undergoes ring closure.
- García, Alberto,Paz, Sonia,Domínguez, Domingo
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p. 665 - 667
(2007/10/03)
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- Chiral aryl sulfonyl hydantoins as hypoglycemic agents
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Some novel chiral sulfonyl hydantoin derivatives 2a-e and 3a-e have been prepared. p-Toluenesulfonyl chloride on treatment with L-amino acids in presence of K2CO3/H2O yielded N-(p-toluensulfonyl-)amino acids 1a-e which were cyclized in presence of NH4SCN / Ac2O to afford 1-(p-toluenesulfonyl)-5-substituted-2-thiohydantoins 2a-e. These compounds were oxidized with HNO3 to yield 1-(p-toluenesulfonyl)-5-substituted hydantoins 3a-e. The enantiomeric ratios of 3a-e were determined by 1H NMR spectroscopy using Eu(hfc)3. The antidiabetic activity of 3a-d has been determined.
- Ahmad, Roshan,Jabeen, Rukhsana,Zia-Ul-Haq, Mohammad,Nadeem, Humaira,Duddeck, Helmut,Verspohl, Eugen J.
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p. 203 - 207
(2007/10/03)
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- Protease inhibitors - Part 5. Alkyl/arylsulfonyl- and arylsulfonylureido-/arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase
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Reaction of alkyl/arylsulfonyl halides with glycine afforded a series of derivatives which were first N-benzylated by treatment with benzyl chloride, and then converted to the corresponding hydroxamic acids with hydroxylamine in the presence of carbodiimide derivatives. Other derivatives were obtained by reaction of N-benzyl-glycine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, followed by conversion of their COOH group into the CONHOH moiety, as mentioned above. The 90 new compounds reported here were assayed as inhibitors of the Clostridium histolyticum collagenase (EC 3.4.24.3), a zinc enzyme which degrades triple helical regions of native collagen. The prepared hydroxamate derivatives were generally 100-500 times more active than the corresponding carboxylates. In the series of synthesized hydroxamates, substitution patterns leading to the best inhibitors were those involving perfluoroalkylsulfonyl- and substituted- arylsulfonyl moieties, such as pentafluorophenylsulfonyl, 3- and 4- carboxyphenylsulfonyl-, 3-trifluoromethyl-phenylsulfonyl or 1- and 2-naphthyl among others. Thus, it seems that similarly to the matrix metalloproteinase (MMP) hydroxamate inhibitors, Clostridium histolyticum collagenase inhibitors should incorporate hydrophobic moieties at the P1, and P2, sites, whereas the α-carbon substituent may be a small and compact moiety (such as H. for the Gly derivatives reported here). Such compounds might lead to the design of collagenase inhibitor-based drugs useful as anti-cancer, anti-arthritis or anti-bacterial agents for the treatment of corneal keratitis. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Scozzafava, Andrea,Supuran, Claudiu T.
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p. 299 - 307
(2007/10/03)
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- Asymmetric Synthesis of Functionalized Secondary Alcohols by Catalytic Ring-Cleavage Reactions of Cyclic Acetals Derived from (R)-1,3-Butanediol
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In the presence of a catalytic amount (0.1-0.2 molar amount) of a 2-phenyl-1,3,2-oxazaborolidin-5-one, prepared by the reaction of dichlorophenylborane and N-(trifluoromethylsulfonyl)-L- phenylalanine, and enol silyl ethers ((R2)2C=C-(R3)OTMS; R3 = t-BuS, EtS, EtO, Ph) (1.1-1.5 molar amount), chiral cyclic acetals 6 derived from (R)-1,3-butanediol and aldehydes undergo an efficient ring-cleavage reaction with the inversion of the stereochemistry at the acetal carbon to give the anti isomer of the corresponding products with high stereoselectivity. The reaction is applicable to acetals derived from aromatic, aliphatic, and α,β-unsaturated aldehydes. Not only enol silyl ethers, but also methallyltrimethylsilane and allyltributyltin, can be employed as nucleophiles, leading to the selective formation of the anti isomer of the corresponding allylated ring-cleavage products. Removal of the chiral auxiliary from these ring-cleavage products by a two-step sequence ((i) PCC (ii) Bn2NH2(CF3CO2)) furnishes enantiomerically enriched β-hydroxy carbonyl compounds and homoallyl alcohols. A modest level of kinetic resolution is observed in the ring cleavage of a racemic acetal catalyzed by a phenylboron compound derived from N-mesyl-L-phenylalanine.
- Kinugasa, Motoharu,Hanada, Toshiro,Egusa, Takayuki,Fujita, Katsuhiro,Oku, Akira
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p. 3639 - 3650
(2007/10/03)
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- Sulfonyl transfer from imidazoles
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The rate constants for the non-catalyzed bimolecular substitution of 1-tosylimidazole, 1, 1-tosyl-3-methylimidazolium, 2, and 1-tosyl-2,3-dimethylimidazolium, 3, chlorides by primary aliphatic amines (5 n Nu=0.5, 0.5 and 0.6 respectively.Despite large variations in the reactivity, 6 powers of ten from 1 to 2, and in the leaving group pK's, 7 units from 2 to 1, the nucleophile effect is found to be nearly constant.The nucleofuge effect is also independent of the nucleophile; apparent βL-coefficients of approximately - 0.9 are observed whatever the amine.These data correspond to rate-limiting transition states where there is small but significant bonding of the sulfonyl with the entering amines and with the leaving imidazoles.These results strongly suggest a concerted single-step displacement mechanism; however, a stepwise mechanism involving a very unstable and very short-lived pentahedric intermediate cannot be strictly ruled out.These findings are compared with those on other acyl transfers.
- Monjoint, P.,Ruasse, M. F.
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p. 356 - 360
(2007/10/02)
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- Substrate Specificity and Stoichiometry of Nα-Benzyloxycarbonyl Amino Acid Urethane Hydrolase from Streptococcus faecalis R ATCC 8043
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The substrate specificity of a new enzyme, Nα-benzyloxycarbonyl amino acid urethane hydrolase, was investigated.The enzyme hydrolyzed Nα-benzyloxycarbonyl-glycine and -alanine, and Nα-benzoyl-glycine and -alanine.Nα-benzyloxycarbonyl-glycine was hydrolyzed to give equimolar benzyl alcohol and glycine.Equimolar benzoic acid and glycine were produced from Nα-benzoyl-glycine by the enzyme reaction.The Km, k0, and k0/Km values were measured for several substrates.The k0 values varied widely with the amino acid residues.Nα-benzyloxycarbonyl-glycine and Nα-benzoyl-glycine produced relatively small changes in the Km values (0.36 ca. 0.10 mM) and the k0/Km values (99440 ca. 202000 M-1 sec-1).The rate of hydrolysis is significantly affected by electron-supplying substituents on the benzene ring.
- Matsumura, Eiko,Shin, Takashi,Murao, Sawao,Kawano, Tatsu
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p. 973 - 980
(2007/10/02)
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- NUCLEOPHILIC SUBSTITUTION AT SULFONYL SULFUR ATOM : AMINOLYSIS OF 1-TOSYL-3-METHYL IMIDAZOLIUM CHLORIDE IN AQUEOUS MEDIUM.
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Kinetics of the reaction of 1-tosyl-3-methyl-imidazolium chloride with various amines were measured to examine the nature of sulfonyl transfer in enzymatic reactions.The activations parameters and the value of the Broensted exponent, β=0.48, are consistent with a small degree of bonding between the entering amine and the sulfur atom in the transition state.Similarities in the nucleophilic behavior of sulfonyl and carbonyl groups are detected.
- Monjoint, Pierre,Ruasse, Marie-Francoise
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p. 3183 - 3186
(2007/10/02)
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