Maleamic and Citraconamic Acids, Methyl Esters, and Imides

Mehta, Nariman B.; Phillips, Arthur P.; Lui, Florence Fu; Brooks, R. L.

doi:10.1021/jo01076a038

Cited by 164 publications

(59 citation statements)

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“…[45] Although ferrocenyl containing N-substituted maleimide derivatives were prepared by this method, [33] the rather harsh conditions are not compatible with most organometallic compounds. Complexes 6-8 were then synthesized according to the method described by Walker [46] by utilizing the Mitsunobu reaction.…”

Section: Resultsmentioning

confidence: 99%

Cysteine‐Specific, Covalent Anchoring of Transition Organometallic Complexes to the Protein Papain from Carica papaya

et al. 2007

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Site-directed and covalent introduction of various transition metal-organic entities to the active site of the cysteine endoproteinase, papain, was achieved by treatment of this enzyme with a series of organometallic maleimide derivatives specially designed for the purpose. Kinetic studies made it clear that time-dependent irreversible inactivation of papain occurred in the presence of these organometallic maleimides as a result of Michael addition of the sulfhydryl of Cys25. The rate and mechanism of inactivation were highly dependent on the structure of the organometallic entity attached to the maleimide group. Combined ESI-MS and IR analysis indicated that all the resulting papain adducts contained one organometallic moiety per protein molecule. This confirmed that chemospecific introduction of the metal complexes was indeed achieved. Thus, three novel reagents for heavy-atom derivatization of protein crystals, which include ruthenium, rhenium and tungsten, are now available for the introduction of electron-dense scatterers for phasing of X-ray crystallographic data.

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Section: Resultsmentioning

confidence: 99%

Cysteine‐Specific, Covalent Anchoring of Transition Organometallic Complexes to the Protein Papain from Carica papaya

et al. 2007

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“…BMI was also synthesized according to procedures reported in the literature, 17 with some modifications. The procedure may be divided into two steps: (1) To a round-bottom flask, equipped with mechanical stirrer, dropping funnel, and thermometer, maleic anhydride (29.4 g, 0.3 mol) in 600 mL ether was added, then n-butylamine (21.9 g, 0.3 mol) in 360 mL ether was added at 0°C with vigorous stirring for 2 h, and the solution was stirred continuously for another hour.…”

Section: Preparation Of Bmimentioning

confidence: 99%

Spontaneous copolymerization of N‐butyl maleimide and ethyl α‐phenyl acrylate with high alternating tendency

Liu

Huang

2004

J of Applied Polymer Sci

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ABSTRACT:The copolymerization of N-butyl maleimide (BMI) and ethyl ␣-phenyl acrylate (EPA) was successfully carried out without an initiator. A high alternating tendency was observed. The Q, e values were derived by Alfrey-Price equations: Q ϭ 0.09, e ϭ 0.81 for BMI and Q ϭ 0.21, e ϭ Ϫ0.5 for EPA, and the monomer reactivity ratios were r BMI ϭ 0.15 Ϯ 0.01 and r EPA ϭ 0.18 Ϯ 0.08, respectively. In this system BMI was donor and EPA was acceptor. The maximum copolymerization rate and molecular weight appeared at 70 mol % (BMI) in the feed ratio. The spontaneous alternating copolymerization was considered to be completed by a contact-type charge-transfer complex formed by the monomer pairs.

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“…Solvents and reagents were reagent-grade, purchased from commercial suppliers, and used without further purification unless otherwise stated. The following compounds were prepared according to literature procedures: 4-bromophenylalanine (12) [57], N-substituted maleimides [58], 4-toluenesulfinic acid [59], cyclopropylmagnesium bromide [60], and methyl (À)-d-mandelate [61]. THF and Et 2 O were freshly distilled from sodium benzophenone ketyl, CH 2 Cl 2 from CaH 2 .…”

Section: Experimental Partmentioning

confidence: 99%

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Obst¹,

Betschmann²,

Lerner³

et al. 2000

HCA

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A novel class of nonpeptidic, active, and selective thrombin inhibitors has resulted from X‐ray‐structure‐based design and subsequent improvement of the initial lead molecules. These inhibitors possess a bi‐ or tricyclic central core structure with attached side chains to reach the three binding pockets (selectivity S1 pocket, distal D pocket, and proximal P pocket) present in the active site of the enzyme. The key step in the preparation of these compounds is the 1,3‐dipolar cycloaddition between an azomethine ylide, prepared in situ by the decarboxylative method from an aromatic aldehyde and an α‐amino acid, with an N‐substituted maleimide (e.g., see Schemes 1 and 2). All potent inhibitors contain an amidinium residue in the side chain for incorporation into the S1 pocket, which was introduced in the last step of the synthesis by a Pinner reaction. The compounds were tested in biological assays for activity against thrombin and the related serine protease trypsin. The first‐generation lead compounds (±)‐11 and (±)‐19 (Scheme 1) with a bicyclic central scaffold showed Ki values for thrombin inhibition of 18 μM and 0.67 μM, respectively. Conformationally more restricted second‐generation analogs (Scheme 2) were more active ((±)‐22i: Ki=90 nM (Table 1)); yet the selectivity for thrombin over trypsin remained weak. In the third‐generation compounds, a small lipophilic side chain for incorporation into the hydrophobic P pocket was introduced (Schemes 7 and 8). Since this pocket is present in thrombin but not in trypsin, an increase in binding affinity was accompanied by an increase in selectivity for thrombin over trypsin. The most selective inhibitor (Ki=13 nM, 760‐fold selectivity for thrombin over trypsin; Table 2) was (±)‐1 with an i‐Pr group for incorporation into the P pocket. Optical resolution of (±)‐1 (Scheme 9) provided (+)‐1 with a Ki value of 7 nM and a 740‐fold selectivity, whereas (−)‐1 was 800‐fold less active (Ki=5.6 μM, 21‐fold selectivity). The absolute configuration of the stronger‐binding enantiomer was assigned based on the X‐ray crystal structure of the complex formed between thrombin and this inhibitor. Compound (+)‐1 mimics the natural thrombin substrate, fibrinogen, which binds to the enzyme with the Ph group of a phenylalanine (piperonyl in (+)‐1) in the distal D pocket, with the i‐Pr group of a valine (i‐Pr in (+)‐1) in the proximal P pocket, and with a guanidinium side chain of an arginine residue (phenylamidinium group in (+)‐1) in the selectivity S1 pocket of thrombin. A series of analogs of (±)‐1 with the phenylamidinium group replaced by aromatic and aliphatic rings bearing OH or NH2 groups (Schemes 10 – 14) were not effectively bound by thrombin. A number of X‐ray crystal‐structure analyses of free inhibitors confirmed the high degree of preorganization of these compounds in the unbound state. Since all inhibitors prefer similar modes of association with thrombin, detailed information on the strength of individual intermolecular bonding interactions and their incremental con...

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Maleamic and Citraconamic Acids, Methyl Esters, and Imides

Cited by 164 publications

References 0 publications

Cysteine‐Specific, Covalent Anchoring of Transition Organometallic Complexes to the Protein Papain from Carica papaya

Cysteine‐Specific, Covalent Anchoring of Transition Organometallic Complexes to the Protein Papain from Carica papaya

Spontaneous copolymerization of N‐butyl maleimide and ethyl α‐phenyl acrylate with high alternating tendency

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

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