- REGIOCHEMICALLY CONTROLLED SYNTHESES OF 3-HYDROXYNAPHTO CYCLOBUTENE BY VICINAL DIESTER DIANION CONDENSATION.
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Utilisation of the dianion derived from dimethyl trans-1,2-cyclobutane dicarboxylate allows for the rapid construction of an unsymmetric naphto cyclobutene by two different routes.
- Noire, Paul D.,Franck, Richard W.
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Read Online
- Performance comparison of two cascade reaction models in fluorescence off-on detection of hydrogen sulfide
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Comparative studies on the performances of two cascade reaction based fluorescent H2S probes are reported. These probes were also designed to address the solubility issues of existing probes. The Reso-N3 probe favors the H2S mediated azide-to-amine reduction followed by a cyclization to release the resorufin fluorophore. Reso-Br undergoes a bromide-to-thiol nucleophilic substitution followed by a similar cyclization releasing the same fluorophore. Reso-N3 exhibited lower background fluorescence and better H2S sensing behavior in water compared to Reso-Br. Reso-Br underwent hydrolysis in aqueous buffer conditions (pH = 7.4) while, Reso-N3 was quite stable. Reso-N3 displayed high selectivity and sensitivity towards H2S. Live cell imaging of the species by the probe was also established. This journal is
- Saha, Tanmoy,Kand, Dnyaneshwar,Talukdar, Pinaki
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- Extension of the polyanionic cosalane pharmacophore as a strategy for increasing anti-HIV potency
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The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as well as an undefined postattachment event prior to reverse transcription. Several cosalane analogues having an extended polyanionic 'pharmacophore' were designed based on a hypothetical model of the binding of cosalane to CD4. The analogues were synthesized, and a number of them displayed anti-HIV activity. One of the new analogues was found to possess enhanced potency as an anti-HIV agent relative to cosalane itself. Although the new analogues inhibited both HIV-1 and HIV-2, they were more potent as inhibitors of HIV-1 than HIV-2. Mechanism of action studies indicated that the most potent of the new analogues inhibited fusion of the viral envelope with the cell membrane at lower concentrations than it inhibited attachment, suggesting inhibition of fusion as the primary mechanism of action.
- Cushman, Mark,Insaf, Shabana,Paul, Gitendra,Ruell, Jeffrey A.,De Clercq, Erik,Schols, Dominique,Pannecouque, Christophe,Witvrouw, Myriam,Schaeffer, Catherine A.,Turpin, Jim A.,Williamson, Karen,Rice, William G.
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Read Online
- Copper-promoted direct amidation of isoindolinone scaffolds by sodium persulfate
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Isoindolinones are ubiquitous structural motifs in natural products and pharmaceuticals. Establishing an efficient method for structural modification of isoindolinones could significantly facilitate new drug development. Herein, we describe copper-promoted direct amidation of isoindolinone scaffolds mediated by sodium persulfate. The method exhibits mild reaction conditions and high site-selectivity, and enables the structural modification of the drug indobufen ester with various amides with yields of 49 to 98%. It is also gram-scalable. Additionally, the reaction mechanism appears to involve a radical and a carbocationic pathway.
- Lai, Huifang,Lin, Jin,Xu, Jiexin,Zha, Daijun
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p. 7621 - 7626
(2021/09/22)
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- Design of Chiral NHC-Carboxylates as Potential Ligands for Pd-Catalyzed Enantioselective C?H Activation
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Despite numerous efforts, the synthesis of scalemic carbo- and heterocycles through Pd0-catalyzed C(sp3)?H activation employing chiral ancillary ligands or chiral bases is still limited. Inspired by the recently reported outstanding performance of IBiox-type NHC ligands and bifunctional ligands in similar transformations, a new class of bifunctional NHC-ligands bearing a pendant carboxylate group was designed. A library of 10 imidazolium-carboxylic acids was obtained in five to six steps from enantiopure l-tert-leucinol. In addition, four well-defined Pd(DMBPA)-NHC palladacycles were synthesized in good to excellent yields from the corresponding imidazolium precursors. These complexes were tested in a prototypical C(sp3)?H arylation reaction, and the most active one afforded the indoline product in low yield but significant enantioselectivity. These new bifunctional NHCs could find broader applications in catalytic enantioselective transformations occurring under milder conditions.
- Niggli, Nadja E.,Baudoin, Olivier
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- One-pot method to construct isoindolinones and its application to the synthesis of DWP205109 and intermediate of Lenalidomide
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Herein a practical and efficient system for concise synthesis of isoindolinones is described by using substituted methyl 2-(halomethyl)benzoates and substituted amines. Structurally various methyl 2-(halomethyl)benzoates and amines were transformed into isoindolinones 80–99% yield and purity in catalyst-free and solvent-free conditions. The method has a wide substrate scope. The synthetic utility of the one-pot reaction was demonstrated by the concise syntheses of Lenalidomide intermediate and DWP205190.
- Liu, Jinbiao,Lu, Bowei,Lu, Junrui,Wang, Hongbo,Xie, Zhiqiang,Zhong, Kaikai
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supporting information
(2021/06/07)
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- Polycyclic pyridone derivative, pharmaceutical composition and application thereof
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The invention belongs to the field of medicines, and relates to a polycyclic pyridone derivative, a pharmaceutical composition and application thereof. The polycyclic pyridone derivative is a compound as shown in a formula (I) or a stereoisomer, a tautomer, a nitric oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrugs of the compound as shown in the formula (I). Compared with the existing similar compounds, the compound disclosed by the invention not only can well inhibit the replication of influenza viruses, but also has lower cytotoxicity.
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Paragraph 0127; 0135-0136
(2021/05/01)
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- Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio
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The farnesoid X receptor (FXR) is a promising therapeutic target for nonalcoholic steatohepatitis (NASH) and other bile acid related diseases because it plays a critical role in fibrosis, inflammation and bile acid homeostasis. Obeticholic acid (OCA), a FXR agonist which was synthesized from chenodeoxycholic acid, showed desirable curative effects in clinical trials. However, the pruritus which was the main side effect of OCA limited its further applications in NASH. Although pruritus was also observed in the clinical trials of non-steroidal FXR agonists, the proportion of patients with pruritus was much smaller than that of OCA. Thus, we decided to develop non-steroidal FXR agonists and discovered a series of novel FXR agonists which were synthesized from GW4064 by replacing the stilbene group with ketoxime ether. Encouragingly, in the following biological tests, our target compounds 13j and 13z not only showed potent FXR agonistic activities in vitro, but also effectively promoted the expression of target genes in vivo. More importantly, in the pharmacokinetic experiments, compounds 13j and 13z displayed high liver/blood ratio characteristics which were helpful to reduce the potential side effects which were caused by prolonged systemic activation of FXR. In summary, our compounds were good choices for the development of non-steroidal FXR agonists and were deserved further investigation.
- Gu, Yipei,Leng, Ying,Ning, Mengmeng,Shen, Jianhua,Tang, Xuehang,Yan, Hongyi,Ye, Yangliang
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- Synthesis and Anti-Influenza Virus Effects of Novel Substituted Polycyclic Pyridone Derivatives Modified from Baloxavir
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In this work, a series of novel substituted polycyclic pyridone derivatives were designed and synthesized as potent anti-influenza agents. The cytopathic effect (CPE) assay and cytotoxicity assay indicated that all of the compounds possessed potent anti-influenza virus activity and relatively low cytotoxicity; some of them inhibited the replication of influenza A virus (IAV) at picomolar concentrations. Further studies revealed that, at a concentration of 3 nM, three compounds (10a, 10d, and 10g) could significantly reduce the M2 RNA amounts and M2 protein expression of IAV and inhibit the activity of RNA-dependent RNA polymerase (RdRp). Among them, (R)-12-(5H-dibenzo[a,d][7]annulen-5-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (10a) was found to be a promising anti-influenza drug candidate with good human liver microsomal stability, as well as with better selectivity index and oral bioavailability than Baloxavir.
- Chen, Dawei,Gao, Zhenxiong,Hou, Jinqiang,Jiang, Yuyang,Tang, Lin,Wu, Weibin,Yan, Haiyan,Zhang, Cunlong
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supporting information
p. 14465 - 14476
(2021/10/12)
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- Synthesis of Disulfide-Bridged N-Phenyl-N′-(alkyl/aryl/heteroaryl)urea Derivatives and Evaluation of Their Antimicrobial Activities
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The discoveryof new antimicrobial agents is extremely needed to overcome multidrug-resistant bacterial and tuberculosis infections. In the present study, eight novel substituted urea derivatives (10a–10h) containing disulfide bond were designed, synthesized and screened for their in vitro antimicrobial activities on standard strains of Gram-positive and Gram-negative bacteria as well as on Mycobacterium tuberculosis. According to the obtained results, antibacterial effects of the compounds were found to be considerably better than their antimycobacterial activities along with their weak cytotoxic effects. Molecular docking studies were performed to gain insights into the antibacterial activity mechanism of the synthesized compounds. The interactions and the orientation of compound 10a (1,1′-((disulfanediylbis(methylene))bis(2,1-phenylene))bis(3-phenylurea)) were found to be highly similar to the original ligand within the binding pocket E. faecalis β-ketoacyl acyl carrier protein synthase III (FabH). Finally, a theoretical study was established to predict the physicochemical properties of the compounds.
- Dilem Do?an, ?engül,Buran, Sümeyye,G?zde Gündüz, Miyase,?zkul, Ceren,Siva Krishna, Vagolu,Sriram, Dharmarajan
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- Iridium(iii) complex-based electrochemiluminescent probe for H2S
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Since abnormal levels of hydrogen sulphide (H2S) correlate with various diseases, simple methods for its rapid and sensitive detection are highly required. Herein, we introduce a new electrochemiluminescent probe 1 for H2S based on a cyclometalated iridium(iii) complex. o-(Azidomethyl)benzoate ester groups on the main ligands of probe 1 react selectively with H2S, resulting in cascade reactions involving H2S-mediated reduction and intramolecular cyclization/ester cleavage. With this structural change induced by H2S, the intrinsic electrochemiluminescence (ECL) of 1 decreased greatly due to the unfavourable electron transfer of a tripropylamine (TPA) radical. Probe 1 showed a high ECL turn-off ratio and good selectivity for H2S over various anions and biothiols. The sensing mechanism of H2S was elucidated using1H NMR spectroscopy and MALDI-TOF mass spectrometry analyses.
- Park, Joonho,Kim, Taemin,Kim, Hoon Jun,Hong, Jong-In
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p. 4565 - 4573
(2019/04/05)
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- Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine
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The histone methyltransferase SET7/9 methylates not only histone but also non-histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups. Among them, the compound bearing a 2-hydroxy group showed the most potent activity. On the other hand, a 3-hydroxy group or another hydrophilic functional group such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of the hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in the complex with 2-hydroxycyproheptadine. These results are expected to be helpful for further structure-based development of SET7/9 inhibitors.
- Hirano, Tomoya,Fujiwara, Takashi,Niwa, Hideaki,Hirano, Michitake,Ohira, Kasumi,Okazaki, Yusuke,Sato, Shin,Umehara, Takashi,Maemoto, Yuki,Ito, Akihiro,Yoshida, Minoru,Kagechika, Hiroyuki
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p. 1530 - 1540
(2018/08/01)
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- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to macrocyclic α-keto amide derivatives and their use as therapeutic agents.
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Paragraph 0372
(2018/09/25)
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- Palladium-Catalyzed, ortho-Selective C-H Halogenation of Benzyl Nitriles, Aryl Weinreb Amides, and Anilides
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A palladium-catalyzed, ortho-selective C-H halogenation methodology is reported herein. The highlight of the work is the highly selective C(sp2)-H functionalization of benzyl nitriles in the presence of activated C(sp3)-H bond, which results in good yields of the halogenated products with excellent regioselectivity. Along with benzyl nitriles, aryl Weinreb amides and anilides have been evaluated for the transformation using aprotic conditions. Mechanistic studies yield interesting aspects with respect to the pathway of the reaction and the directing group abilities.
- Das, Riki,Kapur, Manmohan
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p. 1114 - 1126
(2018/06/18)
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- Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short synthesis of doxepin
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A novel and efficient synthesis of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular ortho-acylation from readily available 2-(phenoxymethyl)benzoic acids was developed. The method takes advantage of a newly developed cooperative system consisting of sustainable FeCl2 and Cl2CHOCH3 as the key components. This methodology is compatible with a wide variety of functional groups in good to excellent yields and high regioselectivity. The synthetic application of new protocol was extended to the synthesis of known tricyclic drug doxepin as well as a small library of oxepin based derivatives. For the first time, the obtained dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-living nematode Caenorhabditis elegans as an effective and cost-efficient model system for anthelmintic discovery.
- Scoccia, Jimena,Castro, M. Julia,Faraoni, M. Belén,Bouzat, Cecilia,Martín, Víctor S.,Gerbino, Darío C.
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supporting information
p. 2913 - 2922
(2017/04/26)
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- Design, synthesis and biological evaluation of novel hamamelitannin analogues as potentiators for vancomycin in the treatment of biofilm related Staphylococcus aureus infections
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Staphylococcus aureus is a frequent cause of biofilm-related infections. Bacterial cells within a biofilm are protected from attack by the immune system and conventional antibiotics often fail to penetrate the biofilm matrix. The discovery of hamamelitannin as a potentiator for antibiotics, recently led to the design of a more drug-like lead. In the present study, we want to gain further insight into the structure–activity relationship (S.A.R.) of the 5-position of the molecule, by preparing a library of 21 hamamelitannin analogues.
- Vermote, Arno,Brackman, Gilles,Risseeuw, Martijn D.P.,Coenye, Tom,Van Calenbergh, Serge
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p. 4563 - 4575
(2016/09/13)
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- HAMAMELITANNIN ANALOGUES AND USES THEREOF
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The present invention relates to hamamelitannin analogues, pharmaceutical compositions comprising the same, and combinations thereof with anti-microbial agents such as antibiotics or disinfectants. It in particular relates to the use of the compounds, compositions and combinations according to this invention in human or veterinary medicine, more in particular for use in the prevention and/or treatment of bacterial infections, such as Staphylococcusaureus infections, in humans or animals.
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Page/Page column 152
(2016/01/25)
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- INHIBITORS OF HEPATITIS C VIRUS POLYMERASE
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The present invention provides, among other things, compounds represented by the general Formula I: (I) and pharmaceutically acceptable salts thereof, wherein L and A (and further substituents) are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.
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Paragraph 337; 338
(2016/10/11)
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- PYRROLIDINE AMIDE COMPOUNDS AS HISTONE DEMETHYLASE INHIBITORS
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The present invention relates to compounds of formula (I) useful as inhibitors of one or more histone demethylses, such as KDM5. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and the compounds for use in methods for the treatment of various disorders. Formula (I): or a salt thereof, wherein: A is selected from the group consisting of:
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Page/Page column 103; 104
(2016/05/02)
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- SUBSTITUTED PYRIDINE COMPOUNDS HAVING HERBICIDAL ACTIVITY
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The present invention provides a substituted pyridine compound of the formula I or an agriculturally suitable salt or N-oxide thereof, wherein the variables in the formula I defined as in the description. Substituted pyridine compounds of formula I are useful as herbicides.
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Page/Page column 102
(2016/05/24)
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- Synthesis and biological evaluation of aryloxyacetamide derivatives as neuroprotective agents
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A series of new aryloxyacetamide derivatives 10a-s and 14a-m are designed and synthesized. Their protective activities against the glutamate-induced cell death were investigated in differentiated rat pheochromocytoma cells (PC12 cells). Most compounds exhibited neuroprotective effects, especially for 10m, 10r, 14b and 14c, which showed potential protection of PC12 cells at three doses (0.1, 1.0, 10 μM). MTT assay, Hoechst 33342/PI double staining, and high content screening (HCS) revealed that pretreatment of the cells with 10m, 10r, 14b and 14c has significantly decreased the extent of cell apoptosis in a dose-dependent manner. The results of western blot analysis demonstrated these compounds suppressed apoptosis of glutamate-induced PC12 cells via caspase-3 pathway. These compounds can be lead compounds for further discovery of neuroprotective agents for treating cerebral ischemic stroke. Basic structure-activity relationships are also presented.
- Zhong, Yan,Xu, Yi,Zhang, Ai-Xia,Li, Xiao-Feng,Xu, Zhao-Ying,Li, Ping,Wu, Bin
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p. 2526 - 2530
(2016/07/07)
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- Synthetic method of doxepin hydrochloride adopting o-halogen methyl benzoate as raw material
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The invention discloses a synthetic method of doxepin hydrochloride adopting o-halogen methyl benzoate as a raw material. The synthetic method comprises: taking the o-methyl benzoate wide in source as a starting raw material, and sequentially carrying out benzyl halogenations, substitution, hydrolysis, cyclization, nucleophilic addition, nucleophilic substitution and neutralization to obtain salazosulfapyridine. In the nucleophilic substitution step of step 7, an organic lithium compound is dissolved in an ether solvent, so that the organic lithium compound and dimethylamine react to form an ammonium lithium salt (see the description), then the ammonium lithium salt is subjected to alkylation reaction with a halogen compound, the yield of the tertiary ammonium is increased, and the yield and purity of the final doxepin hydrochloride can be guaranteed.
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Paragraph 0083; 0084
(2016/10/07)
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- Method for preparing 1-isoindolinone
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The invention discloses a method for preparing 1-isoindolinone. The method includes the steps that (1) methyl o-toluate is weighed and dissolved in carbon tetrachloride, NBS and benzoyl peroxide are added, and backflow reaction is carried out for 2h; after reaction is complete according to TLC detection, cooling, filtering and filter liquor spin-drying are conducted, and accordingly the intermediate of methyl 2-bromomethyl benzoate is obtained; and (2) the methyl 2-bromomethyl benzoate is dissolved in a tetrahydrofuran solution, stronger ammonia water is added dropwise, and the mixture is stirred overnight at an indoor temperature; after the reaction is complete according to TLC detection, spin-drying is performed; after solid water and ethyl acetate are dissolved, extraction is conducted, the organic phase is dried through anhydrous sodium sulfate, and the 1-isoindolinone product is obtained after spin-drying. According to the method, raw materials such as the methyl 2-bromomethyl benzoate, the NBS and the benzoyl peroxide are adopted for synthesizing the compound 1-isoindolinone of a complex structure. The product is high in productive rate, good in crystallization effect and high in purity, and therefore a high-purity standard sample or sample is provided for subsequent chemical and biological experiments.
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Paragraph 0015; 0016; 0017
(2016/11/09)
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- Target hopping as a useful tool for the identification of novel EphA2 protein-protein antagonists
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Lithocholic acid (LCA), a physiological ligand for the nuclear receptor FXR and the G-protein-coupled receptor TGR5, has been recently described as an antagonist of the EphA2 receptor, a key member of the ephrin signalling system involved in tumour growth. Given the ability of LCA to recognize FXR, TGR5, and EphA2 receptors, we hypothesized that the structural requirements for a small molecule to bind each of these receptors might be similar. We therefore selected a set of commercially available FXR or TGR5 ligands and tested them for their ability to inhibit EphA2 by targeting the EphA2-ephrin-A1 interface. Among the selected compounds, the stilbene carboxylic acid GW4064 was identified as an effective antagonist of EphA2, being able to block EphA2 activation in prostate carcinoma cells, in the micromolar range. This finding proposes the "target hopping" approach as a new effective strategy to discover new protein-protein interaction inhibitors. Target hopping: Given the ability of lithocholic acid to recognize FXR, TGR5 and EphA2 receptors, we hypothesized the structural requirements to bind each of these receptors might be similar. We selected a set of commercially available FXR or TGR5 ligands and tested them for their ability to inhibit EphA2 by targeting the EphA2-ephrin-A1 interface. Moreover, a small panel of GW4064 derivatives was synthesized. Copyright
- Tognolini, Massimiliano,Incerti, Matteo,Pala, Daniele,Russo, Simonetta,Castelli, Riccardo,Hassan-Mohamed, Iftiin,Giorgio, Carmine,Lodola, Alessio
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supporting information
p. 67 - 72
(2014/01/17)
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- Tetracarboxylate ligands as new chelates supporting copper(II) paddlewheel-like structures
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Two new ligands N,N,N′,N′-tetrakis(2-methylbenzoic acid)-1,4-diaminomethylbenzene, 5H4, and N,N,N′,N′- tetrakis(2-methylbenzoic acid)-4,4′-diaminomethyldiphenyl, 6H4, carrying four carboxylate groups suitable for bridging dinuclear centers have been prepared and their paddlewheel complexes with copper(II) prepared. The phenyl-bridged ligand 5H4 gives a cyclic octanuclear species [(Cu2)4(5)4], while the diphenyl-bridged ligand 6H4 gives a lantern-like tetranuclear species [(Cu2) 2(6)2]; both were characterized by X-ray crystallography. If the amine functions of 5 are protonated, intramolecular hydrogen bonds position the four carboxylates in such a way as to allow formation of the unusual compound [Cu4(5H2)2Cl]3+ in which a Cu4 square centered by a chloro ligand is sandwiched between two (5H2)2- ligands. The magnetic properties of this compound have been studied and show antiferromagnetic coupling between adjacent coppers (J = -33.7 cm-1).
- Gomila, Antoine,Duval, Sylvain,Besnard, Celine,Kraemer, Karl W.,Liu, Shi-Xia,Decurtins, Silvio,Williams, Alan F.
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p. 2683 - 2691
(2014/03/21)
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- Non-stoichiometric O-acetylation of Shigella flexneri 2a O-specific polysaccharide: Synthesis and antigenicity
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Synthetic functional mimics of the O-antigen from Shigella flexneri 2a are seen as promising vaccine components against endemic shigellosis. Herein, the influence of the polysaccharide non-stoichiometric di-O-acetylation on antigenicity is addressed for the first time. Three decasaccharides, representing relevant internal mono- and di-O-acetylation profiles of the O-antigen, were synthesized from a pivotal protected decasaccharide designed to tailor late stage site-selective O-acetylation. The latter was obtained via a convergent route involving the imidate glycosylation chemistry. Binding studies to five protective mIgGs showed that none of the acetates adds significantly to broad antibody recognition. Yet, one of the five antibodies had a unique pattern of binding. With IC50 in the micromolar to submicromolar range mIgG F22-4 exemplifies a remarkable tight binding antibody against diversely O-acetylated and non-O-acetylated fragments of a neutral polysaccharide of medical importance. This journal is the Partner Organisations 2014.
- Gauthier, Charles,Chassagne, Pierre,Theillet, Francois-Xavier,Guerreiro, Catherine,Thouron, Francoise,Nato, Farida,Delepierre, Muriel,Sansonetti, Philippe J.,Phalipon, Armelle,Mulard, Laurence A.
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supporting information
p. 4218 - 4232
(2014/06/10)
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- Reactions of difluorocarbene with organozinc reagents
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Reactions of difluorocarbene with benzyl and alkylzinc halides leading to fluorinated organozinc species have been described. The generated α-difluorinated organozinc reagents are reasonably stable in solution and can be quenched with external electrophiles (iodine, bromine, proton), affording compounds containing the CF2 fragment.
- Levin, Vitalij V.,Zemtsov, Artem A.,Struchkova, Marina I.,Dilman, Alexander D.
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supporting information
p. 917 - 919
(2013/03/28)
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- Synthesis of diastereomeric, deoxy and ring-expanded sulfone analogues of aigialomycin D
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Several analogues of the fungal natural product aigialomycin D (AmD) have been synthesised. These include the stereoisomer 5′R,6′S-AmD, 2,4-di-deoxyAmD, 1′,2′,7′,8′-tetrahydroAmD and a 15-membered macrocyclic sulfone. Growth inhibitory activities of these compounds against the HL-60 leukaemic cell line were measured. The ring-expanded sulfone and tetrahydro-analogue were found to have similar IC50 values to the natural product, whereas the 5′R,6′S-stereoisomer was inactive. Energy minimisation of AmD and the synthesised analogues resulted in a range of lowest energy conformers, from planar, open arrangements of the macrocycle in AmD and tetrahydroAmD to bent, L-shaped structures for the sulfone. The synthesis of methyl orsellinate was investigated and optimised as part of this work. A stereodivergent route to both enantiomers of the diol fragment from d-ribose was also achieved.
- Ting, Samuel Z.Y.,Baird, Lynton J.,Dunn, Elyse,Hanna, Reem,Leahy, Dora,Chan, Ariane,Miller, John H.,Teesdale-Spittle, Paul H.,Harvey, Joanne E.
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p. 10581 - 10592
(2013/11/19)
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- Design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates
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We report herein the design, synthesis, and structure-activity relationship studies of conformationally restricted mutilin 14-carbamates based on the structure of SB-222734. The antibacterial activities of these newly synthesized compounds were also evaluated and compared with linezolid and retapamulin. Results showed that most of the target compounds exhibit good potency in inhibiting the growth of Gram-positive bacteria including Methicillin- susceptible Staphylococcus aureus MSSA (MIC: 0.0625-2 μg/mL), Methicillin-resistant S. aureus MRSA (MIC: 0.0625-2 μg/mL), Methicillin-susceptible Staphylococcus epidermidis MSSE (MIC: 0.0625-2 μg/mL), Methicillin-resistant S. epidermidis MRSE (MIC: 0.0625-2 μg/mL), and Streptococcus pneumonia (MIC: 0.0625-4 μg/mL). In particular, three remarkable compounds of this series (12l, 12m, and 21l) exhibited comparable in vitro antibacterial profiles to that of retapamulin.
- Fu, Liqiang,Liu, Xin,Ling, Chenyu,Cheng, Jianjun,Guo, Xingsheng,He, Huili,Ding, Shi,Yang, Yushe
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scheme or table
p. 814 - 819
(2012/03/11)
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- Rhodium-catalyzed asymmetric hydrogenation of olefins with PhthalaPhos, a new class of chiral supramolecular ligands
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A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (Phthala- Phos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2- acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1- yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3- phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect.
- Pignataro, Luca,Boghi, Michele,Civera, Monica,Carboni, Stefano,Piarulli, Umberto,Gennari, Cesare
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supporting information; experimental part
p. 1383 - 1400
(2012/03/27)
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- Expanding the structural repertoire of β/α Ant-Pro (anthranilic acid-proline) oligomers into γ/α 2-Amb-Pro (2-aminomethyl benzoic acid-proline) oligomers
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In this article, we report a novel class of heterogeneous synthetic oligomers featuring the conformationally constrained amino acid residues - 2-aminomethyl benzoic acid (2-Amb) and proline (Pro) in repeating sequences. Oligomers as large as hexadecamers featuring the conformationally restricted γ/α 2-Amb-Pro motif have been assembled using solution-phase Boc strategy, following multi-step synthetic sequences starting from the commercially available O-toluic acid. EDC-mediated peptide coupling has been found to be optimum for the assembly of the relatively non-polar oligomers, which could be readily purified by the standard column chromatographic purification procedures. This study offers considerable prospects of expanding the structural repertoire of β/α Ant-Pro motif, which has been described earlier to assume right-handed helical architecture displaying robust nine-membered-ring closed network of hydrogen-bonding interactions, into γ/α 2-Amb-Pro motif.
- Ramesh, Veera V.E.,Priya, Gowri,Rajamohanan,Hofmann, Hans-J?rg,Sanjayan, Gangadhar J.
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scheme or table
p. 4399 - 4405
(2012/07/27)
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- Chemical synthesis of bioactive siRNA in solution phase by using 2-(azidomethyl)benzoyl as 3′-hydroxyl group protecting group
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A protecting group AZMB was introduced to ribonucleosides 3′-hydroxyl group to facilitate solution phase synthesis of siRNA. The protection and cleavage reaction were carried out in mild conditions, that is protection by acyl chloride and cleavage by triphenylphosphine. The synthesized siRNA showed good biological activity to suppress targeted superoxide dismutase gene expression.
- Huang, Jinyu,Xi, Zhen
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supporting information; experimental part
p. 3654 - 3657
(2012/10/07)
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- Targeting the hinge glycine flip and the activation loop: Novel approach to potent p38α inhibitors
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The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC50 values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.
- Martz, Kathrin E.,Dorn, Angelika,Baur, Benjamin,Schattel, Verena,Goettert, Márcia I.,Mayer-Wrangowski, Svenja C.,Rauh, Daniel,Laufer, Stefan A.
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p. 7862 - 7874
(2012/10/29)
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- METHOD FOR PREPARING OLIGONUCLEOTIDE
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A method for preparing oligonucleotide comprising reacting the compound of Formula (1) with the compound of Formula (2) in a liquid reaction medium under the condition of condensation reaction to obtain the compound of formula (3). In the method according to the present invention, the functional groups are protected by suitable protective groups to only expose the 5′-OH of the compound of Formula (1) (OH-component) and the 3′-phosphate of the compound of Formula (2) (P-component) which are to be connected, so that the condensation reaction is carried out in a liquid reaction medium to bond the OH-component and P-component to obtain DNA or RNA short chain. The method of the present invention does not need a solid phase column and can be carried out in a liquid reaction medium. Thus, oligonucleotides can be synthesized on a large scale.
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- NOVEL COMPOUNDS FOR MODULATION OF ORPHAN NUCLEAR RECEPTOR RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ GAMMA, NR1F3) ACTIVITY AND FOR THE TREATMENT OF CHRONIC INFLAMMATORY AND AUTOIMMUNE DISEASE
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The invention provides modulators for the orphan nuclear receptor RORγ and methods for treating RORγ mediated diseases by administrating these novel RORγ modulators to a human or a mammal in need thereof. Specifically, the present invention provides compounds of Formula (1) and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof.
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- TETRACYCLIC COMPOUND
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Provided are a tetracyclic compound represented by the formula (I): [in the formula(I),the formula (A) represents a benzene ring or the like, X represents CH or a nitrogen atom, Q represents -O- or the like, R1, R2, and R3 may be the same or different and each represent a hydrogen atom or the like, 1, m, and n each represent an integer from one to the maximum substitutable number of substituents, and R4 and R5 may be the same or different and each represent a hydrogen atom or the like], or a pharmaceutically acceptable salt thereof, and the like.
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Page/Page column 48
(2011/04/25)
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- Alkenylphosphonates: Unexpected products from reactions of methyl 2-[(diethoxyphosphoryl)methyl]benzoate under Horner-Wadsworth-Emmons conditions
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Methyl 2-[(diethoxyphosphoryl)methyl]benzoate reacts with several aldehydes to produce an alkenylphosphonate as the major product, together with varying amounts of the expected Horner-Wadsworth-Emmons product, a 1,2-disubstituted E-alkene. Use of a bulky aldehyde or the tert-butyl ester favours the normal HWE product.
- Baird, Lynton J.,Colomban, Cedric,Turner, Claire,Teesdale-Spittle, Paul H.,Harvey, Joanne E.
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supporting information; experimental part
p. 4432 - 4435
(2011/07/30)
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- Novel compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-gamma (ROR gamma, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune desease
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The invention provides modulators for the orphan nuclear receptor RORγ and methods for treating RORγ mediated diseases by administrating these novel RORγ modulators to a human or a mammal in need thereof. Specifically, the present invention provides compounds of formula (1) or (2) and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof.
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Paragraph 0096
(2013/03/26)
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- Modular assembly of macrocyclic organo-peptide hybrids using synthetic and genetically encoded precursors
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Mix, click, cyclize: Conformationally constrained organo-peptide hybrids can be constructed by a tandem chemoselective reaction between a synthetic molecule and a recombinant protein. Diverse macrocyclic structures were obtained in cyclic, lariat, and protein-tethered configurations by varying the nature of the synthetic and biosynthetic precursors. Copyright
- Smith, Jessica M.,Vitali, Francesca,Archer, Steven A.,Fasan, Rudi
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supporting information; experimental part
p. 5075 - 5080
(2011/06/28)
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- HETEROCYCLYL PYRAZOLOPYRIMIDINE ANALOGUES AS JAK INHIBITORS
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The present invention relates to compounds of formula (I) wherein X1 to X5, Y, Z1 to Z3, and R have the meaning as cited in the description and the claims. Said compounds are useful as JAK inhibitors for the treatment or prophylaxis of immunological, inflammatory, autoimmune, allergic disorders, and immunologically-mediated diseases. The invention also relates to pharmaceutical compositions including said compounds, the preparation of such compounds as well as the use as medicaments.
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Page/Page column 85; 86
(2011/05/06)
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- Novel O-acetylated decasaccharides
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The present invention relates to diversely acetylated decasaccharides of formula (I) representative of two repeating units of Shigella flexneri serotype 2a O-antigen, conjugates and method of preparation thereof. These compounds exhibit antigenic properties and are particularly useful for the diagnosis of Shigella infection. wherein R1 and R2 are as defined in claim 1.
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Page/Page column 22-23
(2011/12/01)
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- From cholapod to cholaphane transmembrane anion carriers: Accelerated transport through binding site enclosure
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Cyclosteroidal "cholaphane" anion transporters show increased activities compared to acyclic "cholapod" analogues.
- Judd, Luke W.,Davis, Anthony P.
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supporting information; experimental part
p. 2227 - 2229
(2010/07/08)
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- Peptide ligation assisted by an auxiliary attached to amidyl nitrogen
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New thiol-containing auxiliaries were developed for peptide ligation. They were placed at the amidyl N-atom in the second amino acid residue of a peptide fragment. With the new auxiliaries, peptide ligation could be conducted at non-Cys and non-Gly sites. Compared to other recently developed auxiliaries, an important feature of the present design was that the new auxiliaries were generally applicable and readily removable.
- Li, Juan,Cui, Hong-Kui,Liu, Lei
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scheme or table
p. 1793 - 1796
(2010/06/13)
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- FREE RADICAL INITIATOR AND METHOD FOR PEPTIDE SEQUENCING USING THE SAME
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The present invention relates to a free radical initiator and a method for peptide sequencing using the same. Compared with diazo or peroxy functionalized precursors, the precursors using the present compounds are chemically more robust and can generate radical species by homolytic cleavage upon thermal activation, enabling sequencing of more various peptides. In addition, the present invention makes it feasible to sequence peptides carrying disulfide bonds.
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- Synthesis of (+)-varitriol analogues via novel and versatile building blocks based on julia olefination
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The synthesis of (+)-varitriol (1) analogues was achieved through, the use of Julia olefination. The potential anticancer properties of 1 coupled with, our interest in developing building blocks that enable olefin formation under the Julia protocol constitute the basis of our research project. Efforts are aimed at the synthesis of building blocks 2 and 3 and to explore their use towards the synthesis of (+)-varit:riol analogues. Herein, we would, like to present the synthesis of building block 3 and its ability to react with variety of substituted aromatic-, heterocyclic- and carbohydrate-derived aldehydes to yield alkene 6 in moderate to good yields with E as the major isomer. The successful, coupling of 2 with (furanoside moieties) aldehydes 5k, 5m and 5n in particular and the obtainment of compound 23 reflect the promise associated with the new strategy.
- Senthilmnrugan, Annamalai,Aidhen, Indrapal Singh
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experimental part
p. 555 - 564
(2010/04/24)
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- DIAZENIUMDIOLATE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
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Compounds of formula (I): wherein: R1 represents a hydrogen atom or a —COOR group, R2 represents a group G or a linear or branched (C1-C6)alkyl group substituted by a group G, wherein G represents a —(CH2)n-A-(CH2)m—B—(CR4R5)p—(CH2)o-R6 group as defined in the description, R3 represents a hydrogen atom, an alkyl group or an NO2 group.
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Page/Page column 4
(2010/12/29)
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- ANTIVIRAL COMPOUNDS AND USE THEREOF
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The invention relates to compounds, pharmaceutical compositions and methods useful for treating viral infection.
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Page/Page column 29
(2009/12/02)
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- Isoindol-1,3-dione and isoindol-1-one derivatives with high binding affinity to β-amyloid fibrils
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Based on the structural features of Indoprofen and PIB, a series of isoindol-1,3-diones 1a-k and isoindol-1-ones 2a-l were designed and synthesized. These 23 compounds were evaluated by competitive binding assay against aggregated Aβ42 fibrils using [125I]TZDM. All the isoindolone derivatives showed very good binding affinities with Ki values in the subnanomolar range (0.42-0.94 nM). Among them, isoindol-1,3-diones 1i and 1k and isoindol-1-ones 2c and 2i exhibited excellent binding affinities (Ki = 0.42-0.44 and 0.46-0.49 nM) than those of Indoprofen (Ki = 0.52 nM) and PIB (Ki = 0.70 nM). These results suggest that isoindolones could be served as a scaffold for potential AD diagnostic probes to monitor Aβ fibrils.
- Lee, Hyu Ji,Lim, Soo Jeong,Oh, Seung Jun,Moon, Dae Hyuk,Kim, Dong Jin,Tae, Jinsung,Yoo, Kyung Ho
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p. 1628 - 1631
(2008/09/19)
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- Radical reactions with 3H-quinazolin-4-ones: Synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin
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Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone 2, mackinazolinone 3, tryptanthrin 4, luotonin A 5 and rutaecarpine 8 were synthesised by radical cyclisation onto 3H-quinazolin-4-one. This journal is The Royal Society of Chemistry.
- Bowman, W. Russell,Elsegood, Mark R. J.,Stein, Tobias,Weaver, George W.
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p. 103 - 113
(2008/03/14)
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- Carboxylic Acid Compounds and Use Thereof
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Provision of a superior URAT1 activity inhibitor effective for the treatment and the like of a pathology involving uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urinary lithiasis, renal dysfunction, coronary heart disease, ischemic cardiac diseases and the like. A URAT1 activity inhibitor containing a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient: [image] wherein each symbol is as defined in the specification.
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Page/Page column 55
(2010/11/28)
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- PHENYLCARBOXYLIC ACID DERIVATIVES AND USE THEREOF FOR THE TREATMENT OF DIABETES
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The invention relates to compounds of general formula (1): in which R1, R2, R3, R4, R5, A, B, D and E are as defined in Claim 1, and also to the preparation process therefor and the therapeutic use thereof. These compounds can be used in the treatment of pathologies associated with hyperglycaemia.
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Page/Page column 64-65
(2010/02/15)
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