- Biocatalysts from cyanobacterial hapalindole pathway afford antivirulent isonitriles against MRSA
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Abstract: The emergence of resistance to frontline antibiotics has called for novel strategies to combat serious pathogenic infections. Methicillin-resistant Staphylococcus aureus [MRSA] is one such pathogen. As opposed to traditional antibiotics, bacteriostatic anti-virulent agents disarm MRSA, without exerting pressure, that cause resistance. Herein, we employed a thermophilic Thermotoga maritima tryptophan synthase (TmTrpB1) enzyme followed by an isonitrile synthase and Fe(II)-α-ketoglutarate-dependent oxygenase, in sequence as biocatalysts to produce antivirulent indole vinyl isonitriles. We report on conversion of simple derivatives of indoles to their C3-vinyl isonitriles, as the enzymes employed here demonstrated broader substrate tolerance. In toto, eight distinct L-Tryptophan derived α-amino acids (7) were converted to their bioactive vinyl isonitriles (3) by action of an isonitrile synthase (WelI1) and an Fe(II)-α-ketoglutarate-dependent oxygenase (WelI3) yielding structural variants possessing antivirulence against MRSA. These indole vinyl isonitriles at 10 μg/mL are effective as antivirulent compounds against MRSA, as evidenced through analysis of rabbit blood hemolysis assay. Based on a homology modelling exercise, of enzyme-substrate complexes, we deduced potential three dimensional alignments of active sites and glean mechanistic insights into the substrate tolerance of the Fe(II)-α-ketoglutarate-dependent oxygenase. Graphic abstract: [Figure not available: see fulltext.]
- Bunn, Brittney M,Xu, Mizhi,Webb, Chase M,Viswanathan, Rajesh
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Read Online
- Method for synthesizing 1 - methyl - L L-tryptophan (by machine translation)
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The invention relates to a method for synthesizing 1 - methyl - L L-tryptophan. The method mainly solves the technical problems that the existing synthetic method needs to use methyl iodide to cause toxicity, low boiling points, sodium metal, liquid ammonia and the like, and industrial production is difficult. The synthesis method comprises N - t-butoxycarbonyl - L L-tryptophan methyl ester, dimethyl carbonate and potassium carbonate heated and refluxed in N, N - dimethylformamide solution to generate compound 1; compound 1 is heated and reacted in hydrochloric acid aqueous solution to generate the target compound 2.1 - methyl - L L-tryptophan as an amino acid derivative. (by machine translation)
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Paragraph 0008; 0009
(2020/08/02)
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- Pentapeptides for the treatment of small cell lung cancer: Optimisation by Nind-alkyl modification of the tryptophan side chain
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The pentapeptide, tert-Prenyl4th-NH2 (DMePhe-DTrp-Phe-DTrp(N-tert-prenyl)-Leu-NH2), has recently been reported by our group to exhibit properties of substance P (SP) antagonist G against small cell lung cancer (SCLC). In this study, we undertook a systematic structure activity investigation to optimise this lead compound to improve its in vitro anti-tumour activity and biocompatibility. A series of D-tryptophan (D-Trp) derivatives were synthesised, with a range of aliphatic N-alkyl chains (methyl to pentyl) on the indole nitrogen (Nind). These were incorporated into the pentapeptide sequence by substitution of the Nind-tert-prenylated D-Trp 4th residue with the Nind-alkylated D-Trp derivatives. These pentapeptides were significantly more potent than tert-Prenyl4th-NH2, with the Nind-butyl modification generating the most cytotoxic peptides. Compared to tert-Prenyl4th-NH2, a single butyl modification on the 4th D-Trp residue (Butyl4th-NH2) showed a ～3 fold enhancement in cytotoxicity in either the chemo-naive H69 or the DMS79 (originating from a patient treated with chemotherapeutics and radiation therapy) SCLC cell lines. In addition, the di-butylated sequence on the 2nd and 4th D-Trp residues (Butyl2nd,4th-NH2) gave ～4.5 times higher cytotoxicity against the H69 cell line and a ～2 fold increase against the DMS79 cell line, compared to tert-Prenyl4th-NH2. The favoured position for butyl modification was the 4th D-Trp residue, as the Butyl2nd-NH2 peptide gave lower cytotoxicity on both cell lines. Butylated peptide sequences, when exposed to neat mouse plasma for 24 h at 37 °C, were found to resist degradation with >80% remaining intact compared to ～58% for tert-Prenyl4th-NH2. The degradation pathway in plasma occurs via de-amidation of the C-terminus, confirmed by mass spectrometry and RP-HPLC analysis. The butyl modification also conferred resistance to metabolism when tested using S9 liver fraction from mouse. The optimum analogue responsive against the DMS79 cell line was the Butyl4th-NH2 pentapeptide, which revealed a concentration dependent increase in apoptosis: the level of late apoptotic cells rose from ～36% at 2 μM to ～96% at 6 μM, as determined by flow cytometry, compared to the unmodified peptide that showed no such effect. Concluding, the butyl substitutions offered the best perspective for high cytotoxicity, induction of apoptosis and metabolic compatibility thereby comprising an improved broad spectrum SP antagonist candidate for treatment of SCLC.
- Haitham Abusara, Osama,Freeman, Sally,Aojula, Harmesh Singh
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p. 221 - 232
(2017/06/08)
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- 1-methyl tryptophan synthesis method
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The present invention provides a direct and efficient 1-methyl tryptophan synthesis method, and specifically relates to a method for synthesizing 1-methyl tryptophan represented by the following formula I. The method comprises that: in an inert solvent, in the presence of an alkaline agent, tryptophan and a methylating agent CH3X (X is defined in the specification) are subjected to a reaction, and separation is performed to obtain the desired product 1-methyl tryptophan. According to the present invention, the organic solvent is adopted as the reaction medium, the suitable alkaline reagent is adopted as the dehydrogenating agent, the tryptophan reacts with the methyl halide, and the crude product is subjected to extraction, washing, re-crystallization and other operations so as to obtain the high purity 1-methyl tryptophan; and the method has characteristics of good yield, strong selectivity, simple operation, safety, and easy control. The formula I is defined in the specification.
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Paragraph 0047; 0048; 0049
(2016/10/10)
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- Palladium-N-heterocyclic carbene (NHC)-catalyzed asymmetric synthesis of indolines through regiodivergent C(sp3)-H activation: Scope and DFT study
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Two bulky, chiral, monodentate N-heterocyclic carbene ligands were applied to palladium-catalyzed asymmetric C-H arylation to incorporate C(sp3)-H bond activation. Racemic mixtures of the carbamate starting materials underwent regiodivergent reactions to afford different trans-2,3- substituted indolines. Although this CAr-Calkyl coupling requires high temperatures (140-160°C), chiral induction is high. This regiodivergent reaction, when carried out with enantiopure starting materials, can lead to single structurally different enantiopure products, depending on the catalyst chirality. The C-H activation at a tertiary center was realized only in the case of a cyclopropyl group. No C-H activation takes place alpha to a tertiary center. A detailed DFT study is included and analyses of methyl versus methylene versus methine C-H activation is used to rationalize experimentally observed regio- and enantioselectivities.
- Katayev, Dmitry,Larionov, Evgeny,Nakanishi, Masafumi,Besnard, Cline,Kündig, E. Peter
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supporting information
p. 15021 - 15030
(2015/02/19)
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- Total synthesis of (-)-ardeemin
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(Chemical Equation Presented) Total synthesis of potent anti-MDR indole alkaloids (-)-ardeemin and its N-acyl analogues has been accomplished from L-tryptophan with about 2% overall yield in 20 steps. The key step depended on the newly developed three-ste
- He, Bin,Song, Hao,Du, Yu,Qin, Yong
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supporting information; experimental part
p. 298 - 304
(2009/04/07)
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- Model studies of the (6-4) photoproduct photoreactivation: Efficient photosensitized splitting of thymine oxetane units by covalently linked tryptophan in high polarity solvents
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Three covalently linked tryptophan-thymine oxetane compounds used as a model of the (6-4) photolyase-substrate complex have been prepared. Under 290 nm light, efficient splitting of the thymine oxetane with aromatic carbonyl compounds gives the thymine monomer and the corresponding carbonyl compounds by the covalently linked tryptophan via an intramolecular electron transfer, and exhibits a strong solvent dependence: the quantum yield (Φ) is ca. 0.1 in dioxane, and near 0.3 in water. Electron transfer from the excited tryptophan residue to the oxetane unit is the origin of fluorescence quenching of the tryptophan residue, and is more efficient in strong polar solvents. The splitting efficiency of the oxetane radical anion within the tryptophan +-oxetane- species is also solvent-dependent, ranging from ca. 0.2 in dioxane to near 0.35 in water. Thus, the back electron transfer reaction in the charge-separated species would be suppressed in water, but is still a main factor causing low splitting efficiencies in the tryptophan-oxetane systems. In contrast to the tryptophan-oxetane system, fast nonradiation processes are the main causes of low efficiency in the flavin-oxetane system. Hence, nonradiative processes of the excited FADH-, rather than electron transfer to oxetane, may be an important factor for the low repair efficiency of (6-4) photolyase. The Royal Society of Chemistry 2006.
- Song, Qin-Hua,Wang, Hong-Bo,Tang, Wen-Jian,Guo, Qing-Xiang,Yu, Shu-Qin
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p. 291 - 298
(2007/10/03)
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- Investigation of the PDZ domain ligand binding site using chemically modified peptides
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Several chemically modified analogues to a tightly binding ligand for the second PDZ domain of MAGI-3 were synthesized and evaluated for their ability to compete with native peptide ligands. N-methyl scanning of the ligand backbone amides revealed the energetically important hydrogen bonds between the ligand backbone and the PDZ domain. Analogues to the ligand's conserved threonine/serine(-2) residue, involved in a side chain to side chain hydrogen bond with a conserved histidine in the PDZ domain, revealed that the interaction is highly sensitive to the steric structure around the hydroxyl group of this residue. Analogues of the ligand carboxy terminus revealed that the full hydrogen bond network of the GLGF loop is important in ligand binding.
- Novak, Kathleen A.P,Fujii, Naoaki,Guy
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p. 2471 - 2474
(2007/10/03)
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- STEREOSPECIFICITY IN THE PICTET-SPENGLER REACTION. ENANTIOSPECIFIC SYNTHESIS OF (6S,10S)-(-)-5-METHYL-9-OXO-12-BENZYL-6,7,8,9,10,11-HEXAHYDRO-6,10-IMINO-5H-CYCLOOCTINDOLE, A TEMPLATE FOR PREPARATION OF MACROLINE/SARPAGINE ALKALOIDS
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The synthesis of the tetracyclic ketone was carried out in enantiospecific fashion (>98percent ee) via the 1,3-transfer of chirality from Na-methyl, Nb-benzyl tryptophan methyl ester to the trans diastereomer in the Pictet-Spengler reaction.Although the condensation of 14 with aldehyde (15) in refluxing benzene generated the tetrahydro β-carbolines (4b/5b) in a kinetic ratio (72:28), epimerization (C-1) of the cis diastereomer into the trans isomer occurred stereospecifically under acidic conditions.Dieckmann cyclizatin of either the Na-methyl, Nb-benzyl-cis-(+)-5b or trans-(-)-4b diastereomer provided the cis-bicyclo-azanonane system at approximately the same rate, although the β-keto esters were antipodal, in contrast to results reported in the Na-benzyl series by Magnus.
- Zhang, Lin-Hua,Bi, Ying-Zhi,Yu, Fu-Xiang,Menzia, Gerald,Cook, James M.
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p. 517 - 547
(2007/10/02)
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- PICTET-SPENGLER REACTIONS IN APROTIC MEDIA. Nb-BENZYL PROMOTED RETENTION OF OPTICAL ACTIVITY IN THE SYNTHESIS OF AN INDOLO SUBSTITUTED AZABICYCLONONANE, A KEY TEMPLATE FOR THE SYNTHESIS OF MACROLINE ALKALOIDS.
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The Nb-benzyl group (see 7) has been employed in the Pictet-Spengler reaction in refluxing benzene to provide complete retention of optical activity in this process.The tetrahydro-β-carbolines 3b (trans) and 4b (cis) were independently converte
- Zhang, Lin-hua,Cook, James M.
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p. 2795 - 2802
(2007/10/02)
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