- Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues
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Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated Guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.
- Roselli, Mariagrazia,Carocci, Alessia,Budriesi, Roberta,Micucci, Matteo,Toma, Maddalena,Di Cesare Mannelli, Lorenzo,Lovece, Angelo,Catalano, Alessia,Cavalluzzi, Maria Maddalena,Bruno, Claudio,De Palma, Annalisa,Contino, Marialessandra,Perrone, Maria Grazia,Colabufo, Nicola Antonio,Chiarini, Alberto,Franchini, Carlo,Ghelardini, Carla,Habtemariam, Solomon,Lentini, Giovanni
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- Fluorinated Olefinic Lactams: The Case of Amino Acids - Preparation and Mechanistic Studies
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Herein, we report the synthesis of analogues of amino acids with a monofluorovinyl moiety. Interestingly, we have found that cyclization of the obtained products proceeds easily in all cases. The cyclization process has not previously been observed at this reaction stage, and such fluorinated lactams derived from phenylalanine, valine, alanine have not been described before.
- Bartoszak-Adamska, El?bieta,Go?dyn, Mateusz,Koroniak, Henryk,Koroniak-Szejn, Katarzyna,Salamon-Krokosz, Katarzyna,Siod?a, Tomasz
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- Direct Access to Primary Amines from Alkenes by Selective Metal-Free Hydroamination
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Direct and selective synthesis of primary amines from easily available precursors is attractive yet challenging. Herein, we report the rapid synthesis of primary amines from alkenes via metal-free regioselective hydroamination at room temperature. Ammonium carbonate was used as ammonia surrogate for the first time, allowing for efficient conversion of terminal and internal alkenes into linear, α-branched, and α-tertiary primary amines under mild conditions. This method provides a straightforward and powerful approach to a wide spectrum of advanced, highly functionalized primary amines which are of particular interest in pharmaceutical chemistry and other areas.
- Du, Yi-Dan,Chen, Bi-Hong,Shu, Wei
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supporting information
p. 9875 - 9880
(2021/03/29)
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- Donor–Acceptor Complex Enables Alkoxyl Radical Generation for Metal-Free C(sp3)–C(sp3) Cleavage and Allylation/Alkenylation
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The alkoxyl radical is an essential and prevalent reactive intermediate for chemical and biological studies. Here we report the first donor–acceptor complex-enabled alkoxyl radical generation under metal-free reaction conditions induced by visible light. Hantzsch ester forms the key donor–acceptor complex with N-alkoxyl derivatives, which is elucidated by a series of spectrometry and mechanistic experiments. Selective C(sp3)-C(sp3) bond cleavage and allylation/alkenylation is demonstrated for the first time using this photocatalyst-free approach with linear primary, secondary, and tertiary alkoxyl radicals.
- Zhang, Jing,Li, Yang,Xu, Ruoyu,Chen, Yiyun
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supporting information
p. 12619 - 12623
(2017/09/11)
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- A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging
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Background Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with 18F and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo. Materials and methods ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) for PET (positron emission tomography). The resulting radiotracer [18F]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [18F]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5 mg/kg ML5. Results ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 ± 2.0, 19.5 ± 2.8, 2.0 ± 0.2 and 5.7 ± 2.2 nM and 12.5 ± 3.1, 31.5 ± 13.7, 138.0 ± 10.9 and 24.7 ± 2.8 nM. Radiochemical yield of HPLC-purified [18F]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [18F]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10 μM of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [18F]FB-ML5 showed a SUVmean of 0.145 ± 0.064 (n = 6) which decreased to 0.041 ± 0.027 (n = 6) after target blocking (p 18F. [18F]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [18F]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [18F]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs.
- Matusiak, Nathalie,Castelli, Riccardo,Tuin, Adriaan W.,Overkleeft, Herman S.,Wisastra, Rosalina,Dekker, Frank J.,Prély, Laurette M.,Bischoff, Rainer P.M.,Van Waarde, Aren,Dierckx, Rudi A.J.O.,Elsinga, Philip H.
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p. 192 - 202
(2015/02/19)
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- Synthesis of substituted imidazolines by an Ugi/Staudinger/aza-Wittig sequence
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A series of 2-(acetamide-2-yl)-imidazolines (II) with 5 points of diversity were prepared by an Ugi-4CR-Staudinger-aza-Wittig-sequence starting from simple azidoalkylamines. The intramolecular aza-Wittig cyclization between the iminophosphane and the tertiary amide of the Ugi product (I) was effected by short microwave irradiation. Competitive cyclization to the secondary amide was not relevant, however, in some cases subsequent formation of the bicyclic ortho-amidines (III) was observed.
- Welsch, Sebastian J.,Umkehrer, Michael,Kalinski, Cedric,Ross, Günther,Burdack, Christoph,Kolb, Jürgen,Wild, Martina,Ehrlich, Anja,Wessjohann, Ludger A.
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supporting information
p. 1025 - 1029
(2015/02/19)
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- Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers, part I: Core region
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Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthesis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the structure activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against other CYP enzymes and the human pregnane X receptor (PXR) will be discussed.
- Liu, Hongtao,Xu, Lianhong,Hui, Hon,Vivian, Randy,Callebaut, Christian,Murray, Bernard P.,Hong, Allen,Lee, Melody S.,Tsai, Luong K.,Chau, Jennifer K.,Stray, Kirsten M.,Cannizzaro, Carina,Choi, You-Chul,Rhodes, Gerry R.,Desai, Manoj C.
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p. 989 - 994
(2014/02/14)
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- Synthesis of proline analogues as potent and selective cathepsin S inhibitors
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Cathepsin S is a potential target of autoimmune disease. A series of proline derived compounds were synthesized and evaluated as cathepsin S inhibitors. We discovered potent cathepsin S inhibitors through structure-activity relationship studies of proline analogues. In particular, compound 19-(S) showed promising in vitro/vivo pharmacological activities and properties as a selective cathepsin S inhibitor.
- Kim, Mira,Jeon, Jiyoung,Song, Jiyeon,Suh, Kwee Hyun,Kim, Young Hoon,Min, Kyung Hoon,Lee, Kwang-Ok
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p. 3140 - 3144
(2013/06/26)
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- Efficient synthesis of functionalized aziridinium salts
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(Chemical Equation Presented) Various aziridinium salts were efficiently prepared from bromination of a series of backbone substituted N,N-bisubstituted β-amino alcohols and isolated via flash column chromatography. The effect of C-substitution, N-substitution, solvent, leaving group, and counter-anions on formation of the isolable aziridinium salts was investigated. 2009 American Chemical Society.
- Chong, Hyun-Soon,Song, Hyun A.,Dadwal, Mamta,Sun, Xiang,Sin, Inseok,Chen, Yunwei
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supporting information; experimental part
p. 219 - 221
(2010/04/24)
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- METHOD FOR PRODUCING ALCOHOL BY HYDROGENATING LACTONE AND CARBOXYLIC ACID ESTER IN LIQUID PHASE
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Disclosed is a method for producing an alcohol from a lactone or a carboxylic acid ester, which enables to produce an alcohol from a lactone or a carboxylic acid ester under relatively mild conditions with high yield and high catalytic efficiency. This method also enables to produce an optically active alcohol from an optically active lactone or an optically active carboxylic acid ester. Specifically disclosed is a method for producing an alcohol by hydrogen reducing a lactone or a carboxylic acid ester in the presence of a catalyst containing ruthenium and a phosphine compound represented by the following general formula (1): wherein R1 represents a spacer; R2, R3, R4, R5, R6 and R7 independently represent a hydrogen atom, an alkyl group having 1-12 carbon atoms, an aryl group or a heterocyclic group; and R8, R9, R10, R11, R12 and R13 independently represent an alkyl group having 1-12 carbon atoms, an aryl group or a heterocyclic group.
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Page/Page column 16
(2010/01/29)
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- Novel compounds that inhibit dipeptidyl peptidase (DPP-IV) and neprilysin (NEP) and/or angiotensin converting enzyme (ACE)
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This invention relates to novel compounds, compositions containing the compounds, that inhibit dipeptidyl peptidase (especially DPP-IV) and neprilysin (NEP, neutral endopeptidase) as well as dipeptidyl peptidase (especially DPP-IV) and angiotensin converting enzyme (ACE) and/or dipeptidyl Peptidase (especially DPP-IV) and vasopeptidases (especially ACE and NEP). These compounds and pharmaceutical compositions thereof are useful for the treatment as well as the prevention of type 2 diabetes mellitus.
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Page/Page column 12
(2010/10/20)
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- Bismuth(III) chloride catalyzed efficient and selective cleavage of trityl ethers
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A highly selective and efficient protocol has been developed for detritylation using 5 mol% BiCl3 in acetonitrile. The cleavage proceeds at room temperature in high yields and the conditions are mild enough to tolerate a variety of acid-base sensitive functional groups.
- Sabitha, Gowravaram,Reddy, E. Venkata,Swapna,Reddy, N. Mallikarjun,Yadav
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p. 1276 - 1278
(2007/10/03)
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- O-(1-phenylbutyl)benzyloxyacetaldoxime, a versatile reagent for the asymmetric synthesis of protected 1,2-aminoalcohols and 2-hydroxymethyl nitrogen heterocycles
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Addition of organometallic reagents to O-(1-phenylbutyl)benzyloxyacetaldoxime in the presence of boron trifluoride diethyl etherate is highly diastereoselective; the resulting hydroxylamines are readily converted into protected 1,2-aminoalcohols and 2-hydroxymethyl nitrogen heterocycles, including the iminosugar 1,4-dideoxy-1,4-imino-D-ribitol, in high enantiomeric excess.
- Cooper, Tracey S.,Larigo, Alexander S.,Laurent, Pierre,Moody, Christopher J.,Takle, Andrew K.
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p. 1730 - 1732
(2007/10/03)
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- From vicinal azido alcohols to Boc-amino alcohols or oxazolidinones, with trimethylphosphine and Boc2O or CO2
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A practical solution to the problem of converting directly 1,2-azido alcohols to Boc-amino alcohols, without recourse to catalytic hydrogenation, involves the use of Me3P/Boc2O in THF (or CH2Cl2) and aqueous NaOH at rt (90-98% yields). The same azido alcohols can be converted in one-pot to the corresponding oxazolidinones with Boc2O/DMAP/Me3P or even better with CO2 and Me3P under basic catalysis (91-96% yields).
- Ariza, Xavier,Pineda, Oriol,Urpí, Fèlix,Vilarrasa, Jaume
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p. 4995 - 4999
(2007/10/03)
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- Di-tert-butyl dicarbonate and 4-(dimethylamino)pyridine revisited. Their reactions with amines and alcohols
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The reaction of BOC2O in the presence and absence of DMAP was examined with some amines, alcohols, diols, amino alcohols, and aminothiols. Often, unusual products were observed depending on the ratio of reagents, reaction time, polarity of solvent, pK(a) of alcohols, or type of amine (primary or secondary). In reactions of aliphatic alcohols with BOC2O/DMAP, we isolated for the first time carbonic-carbonic anhydride intermediates; this helps explain the formation of symmetrical carbonates in addition to the O-BOC products. In the case of secondary amines, we succeeded to isolate unstable carbamic-carbonic anhydride intermediates that in the presence of DMAP led to the final N-BOC product. The effect of N-methylimidazole in place of DMAP was also examined.
- Basel, Yochai,Hassner, Alfred
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p. 6368 - 6380
(2007/10/03)
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- Process for the preparation of oxazoline compound
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The present invention relates to a process for the preparation of an oxazoline compound which is easily chemically converted to a beta-amino-alpha-hydroxy acid or a gamma-amino-beta-hydroxy acid. The method comprises producing a compound of the following formula (4) using alpha -amino acid. The produced compound (4) is subjected to an intramolecular cyclization to produce an oxazoline compound of the following formula (3). The oxazoline compound (3) is oxidized at a vinyl group with RuCl3 or NaIO4 to produce an oxazoline compound of the following formula (1) which is easily chemically converted to a beta-amino-alpha-hydroxy acid. Alternatively, the oxazoline compound (3) may also be treated with 9-borabiclo[3.3.1]nonane such that a hydroxy group is introduced into the end of the vinyl group of the oxazoline compound(3). The introduced end hydroxy group is oxidized with RuCl3 or NaIO4 to produce an oxazoline compound of the following formula (2) which is easily chemically converted to a gamma-amino-hydroxy acid.
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- HETEROCYCLIC AMIDE COMPOUNDS AND PHARMACEUTICAL USE OF THE SAME
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Heterocyclic amide compounds of the formula (I) STR1 wherein each symbol is as defined in the specification, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof. The heterocyclic amide compounds and pharmacologically acceptable salts thereof of the present invention have superior inhibitory activity against chymase groups in mammals inclusive of human, and can be administered orally or parenterally. Therefore, they are useful as chymase inhibitors and can be effective for the prophylaxis and treatment of various diseases caused by chymase, such as those caused by angiotensin II.
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- On the Double Bond Isostere of the Peptide Bond: Preparation of Modified Di- and Tri-peptides incorporating Proline and Alanine Analogues
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The preparation of some analogues of representative peptides that incorporate double bond isosteres of the sequences, Pro-Gly, Pro-Leu, Pro-Phe, Ala-Gly, and Ala-Ala, are described.The method of synthesis involves selective hydroboronation and oxidation of conjugated enynes, to generate βγ-unsaturated acids, followed by selective α-alkylation in order to introduce a second substituent into the 'peptide' backbone.
- Miles, Nicholas J.,Sammes, Peter G.,Kennewell, Peter D.,Westwood, Robert
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p. 2299 - 2306
(2007/10/02)
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