- Novel camphane-based anti-tuberculosis agents with nanomolar activity
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A series of new amidoalcohols and amidodiols were designed on the base of the camphor scaffold and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and MDR strain 43. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. Small structural changes in the side chain shift the activity from micromolar to nanomolar inhibitory concentrations. Quantitative structure-activity relationship (QSAR) model is derived to guide the further lead optimization. Two hydrogen bond donors and up to three rings in the molecules are optimal for nanomolar activity. The camphane-based amides present novel promising scaffolds for antimycobacterial agents.
- Stavrakov, Georgi,Valcheva, Violeta,Philipova, Irena,Doytchinova, Irini
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- Poly(amino acid)-polyester graft copolymer nanoparticles for the acid-mediated release of doxorubicin
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Biodegradable polymers have emerged as highly effective drug delivery vehicles. We combine N-carboxyanhydride and O-carboxyanhydride ring opening polymerisations to synthesise a poly(amino acid)-polyester graft copolymer capable of encapsulating, and subsequently releasing doxorubicin via acid-mediated hydrolysis. Consequently, the nanoparticles detailed are extremely promising vehicles for the controlled delivery of chemotherapeutic agents.
- Price, Daniel J.,Khuphe, Mthulisi,Davies, Robert P. W.,McLaughlan, James R.,Ingram, Nicola,Thornton, Paul D.
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- Enantioselective biosynthesis of L-phenyllactic acid by whole cells of recombinant Escherichia coli
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Background: L-Phenyllactic acid (L-PLA)—a valuable building block in the pharmaceutical and chemical industry—has recently emerged as an important monomer in the composition of the novel degradable biocompatible material of polyphenyllactic acid. However, both normally chemically synthesized and naturally occurring phenyllactic acid are racemic, and the product yields of reported L-PLA synthesis processes remain unsatisfactory. Methods: We developed a novel recombinant Escherichia coli strain, co-expressing L-lactate dehydrogenase (L-LDH) from Lactobacillus plantarum subsp. plantarum and glucose dehydrogenase (GDH) from Bacillus megaterium, to construct a recombinant oxidation/reduction cycle for whole-cell biotransformation of phenylpyruvic acid (PPA) into chiral L-PLA in an enantioselective and continuous manner. Results: During fed-batch bioconversion with intermittent PPA feeding, L-PLA yield reached 103.8 mM, with an excellent enantiomeric excess of 99.7%. The productivity of L-PLA was as high as 5.2 mM·h?1 per OD600 (optical density at 600 nm) of whole cells. These results demonstrate the efficient production of L-PLA by the one-pot biotransformation system. Therefore, this stereoselective biocatalytic process might be a promising alternative for L-PLA production.
- Zhu, Yibo,Wang, Ying,Xu, Jiayuzi,Chen, Jiahao,Wang, Limei,Qi, Bin
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- Mo–Catalyzed One-Pot Synthesis of N-Polyheterocycles from Nitroarenes and Glycols with Recycling of the Waste Reduction Byproduct. Substituent-Tuned Photophysical Properties
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A catalytic domino reduction–imine formation–intramolecular cyclization–oxidation for the general synthesis of a wide variety of biologically relevant N-polyheterocycles, such as quinoxaline- and quinoline-fused derivatives, and phenanthridines, is reported. A simple, easily available, and environmentally friendly dioxomolybdenum(VI) complex has proven to be a highly efficient and versatile catalyst for transforming a broad range of starting nitroarenes involving several redox processes. Not only is this a sustainable, step-economical as well as air- and moisture-tolerant method, but also it is worth highlighting that the waste byproduct generated in the first step of the sequence is recycled and incorporated in the final target molecule, improving the overall synthetic efficiency. Moreover, selected indoloquinoxalines have been photophysically characterized in cyclohexane and toluene with exceptional fluorescence quantum yields above 0.7 for the alkyl derivatives.
- Hernández-Ruiz, Raquel,Rubio-Presa, Rubén,Suárez-Pantiga, Samuel,Pedrosa, María R.,Fernández-Rodríguez, Manuel A.,Tapia, M. José,Sanz, Roberto
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supporting information
p. 13613 - 13623
(2021/08/23)
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- Trikoveramides A-C, cyclic depsipeptides from the marine cyanobacterium Symploca hydnoides
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Trikoveramides A – C, members of the kulolide superfamily of cyclic depsipeptides, were isolated from the marine cyanobacterium, Symploca hydnoides, collected from Bintan Island, Indonesia. Their planar structures were elucidated by a combination of NMR spectroscopy and HRMS spectral data. The absolute configurations of the amino acid and phenyllactic acid units were confirmed by Marfey's and chiral HPLC analyses, respectively, while the relative stereochemistry of the 3-hydroxy-2-methyl-7-octynoic acid (Hmoya) unit in trikoveramide A was elucidated by the application of the J-based configuration analysis and NOE correlations. The cytotoxic activity of the trikoveramides were evaluated against MOLT-4 human leukemia cells and gave IC50 values of 9.3 μM, 35.6 μM and 48.8 μM for trikoveramide B, trikoveramide C and trikoveramide A, respectively. In addition, trikoveramides A – C showed weak to moderate inhibition in the quorum sensing inhibitory assay based on the Pseudomonas aeruginosa lasB-gfp and rhlA-gfp bioreporter strains.
- Goh, Jun Xian,Katermeran, Nursheena Parveen,Phyo, Ma Yadanar,Tan, Lik Tong
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- Pithohirolide, an antimicrobial tetradepsipeptide from a fungus Pithomyces chartarum
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Pithohirolide (1), a new depsipeptide, was isolated from an ascomycetous fungus Pithomyces chartarum TAMA 581. The planar structure of 1 was elucidated on the basis of NMR and MS analyses and the absolute configuration was determined by the advanced Marfey’s analysis, chiral-phase HPLC analysis, and synthesis of degradation product. Compound 1 possesses a cyclic structure comprising (S)-2-hydroxy-3-phenylpropanoic acid, (S)-3-hydroxy-3-phenylpropanoic acid, (S)-2-hydroxyisovaleric acid, and N-methyl-l-alanine, connected via three ester and one amide linkages. Compound 1 exhibited antimicrobial activity against Staphylococcus aureus and Saccharomyces cerevisiae at MIC 3.1 μg ml?1.
- Zhang, Zhiwei,Zhou, Tao,Xing, Tian,Ishizaki, Takayuki,Okuda, Toru,Oku, Naoya,Igarashi, Yasuhiro
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p. 458 - 463
(2021/05/11)
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- Total synthesis and absolute configuration determination of Ktedonoketone, a benzenoid metabolite from Thermophilic bacterium
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The successful total synthesis of both enantiomers of ktedonoketone allowed us to decipher an unambiguous assignment of absolute configuration of the natural product. The concise synthesis highlights Wacker oxidation and aldol condensation as key steps. In addition to this, the current synthetic route is suitable to access a library of compounds on the similar skeleton as one can use readily available amino acids and Grignard reagents as variants.
- Dandawate, Monica,Choudhury, Rahul,Rama Krishna, Gamidi,Srinivasa Reddy
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supporting information
(2020/10/30)
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- Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) Catalysis
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The chromane nucleus is common to a plenum of bioactive small molecules where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3-fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl phenyl ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.
- Daniliuc, Constantin G.,Gilmour, Ryan,Neufeld, Jessica,Sarie, Jér?me C.,Thiehoff, Christian
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p. 15069 - 15075
(2020/06/17)
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- Semirational Design of Fluoroacetate Dehalogenase RPA1163 for Kinetic Resolution of α-Fluorocarboxylic Acids on a Gram Scale
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Here the synthetic utility of fluoroacetate dehalogenase RPA1163 is explored for the production of enantiomerically pure (R)-α-fluorocarboxylic acids and (R)-α-hydroxylcarboxylic acids via kinetic resolution of racemic α-fluorocarboxylic acids. While wild-type (WT) RPA1163 shows high thermostability and fairly wide substrate scope, many interesting yet poorly or moderately accepted substrates exist. In order to solve this problem and to develop upscaled production, in silico calculations and semirational mutagenesis were employed. Residue W185 was engineered to alanine, serine, threonine, or asparagine. The two best mutants, W185N and W185T, showed significantly improved performance in the reactions of these substrates, while in silico calculations shed light on the origin of these improvements. Finally, 10 α-fluorocarboxylic acids and 10 α-hydroxycarboxylic acids were prepared on a gram scale via kinetic resolution enabled by WT, W185T, or W185N. This work expands the biocatalytic toolbox and allows a deep insight into the fluoroacetate dehalogenase catalyzed C-F cleavage mechanism.
- Chen, Bo,Li, Min,Li, Yanwei,Ma, Ming,Tian, Shaixiao,Tong, Wei,Wang, Jian-Bo,Xu, Guangyu,Yue, Yue,Zhang, Hongxia
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p. 3143 - 3151
(2020/03/23)
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- Stereoselective Modification of N-(α-Hydroxyacyl)-glycinesters via Palladium-Catalyzed Allylic Alkylation
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N-(α-Hydroxyacyl)-glycinesters can be used as excellent nucleophiles in Pd-catalyzed allylic alkylation. The method allows for the stereoselective introduction of a wide range of side chains, including highly functionalized ones. Both diastereomers can be accessed through variation of the reaction conditions. Furthermore, the use of stannylated carbonates introduces vinylstannane motifs, which are eligible for subsequent C-C coupling reactions.
- Horn, Alexander,Kazmaier, Uli
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supporting information
p. 4595 - 4599
(2019/06/27)
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- Learning from Peptides to Access Functional Precision Polymer Sequences
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Functional precision polymers based on monodisperse oligo(N-substituted acrylamide)s and oligo(2-substituted-α-hydroxy acid)s have been synthesized. The discrete sequences originate from a direct translation of side-chain functionality sequences of a peptide with well-studied properties. The peptide was previously selected to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin. The resulting peptidomimetic formulation additives preserve the drug solubilization and release characteristics of the parent peptide. In some cases, superior properties are obtained, reaching up to 40 % higher payloads and 27-times faster initial drug release.
- Maron, Eva,Swisher, Jordan H.,Haven, Joris J.,Meyer, Tara Y.,Junkers, Tanja,B?rner, Hans G.
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supporting information
p. 10747 - 10751
(2019/07/09)
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- Glycerol conversion to high-value chemicals: The implication of unnatural α-amino acid syntheses using natural resources
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Glycerol derivatives are an important class of compounds, which have great applications as basic structural building blocks in organic synthesis. O-Benzylglycerol was oxidised to produce a high-value compound in high yield using a NaOtBu-O2 system. Furthermore, the synthetic utility of the resulting product was demonstrated by its transformation into unnatural α-amino acids, thus showing the valorisation of glycerol biomass.
- Park, Yun Ji,Yang, Jung Woon
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p. 2615 - 2620
(2019/06/03)
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- Heterologous production of asperipin-2a: Proposal for sequential oxidative macrocyclization by a fungi-specific DUF3328 oxidase
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Asperipin-2a is a ribosomally synthesized and post-translationally modified peptide isolated from Asperigillus flavus. Herein, we report the heterologous production of asperipin-2a and determination of its absolute structure. Notably, the characteristic bicyclic structure was likely constructed by a single oxidase containing the DUF3328 domain.
- Ye, Ying,Ozaki, Taro,Umemura, Myco,Liu, Chengwei,Minami, Atsushi,Oikawa, Hideaki
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supporting information
p. 39 - 43
(2019/01/04)
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- A novel D-2-hydroxy acid dehydrogenase with high substrate preference for phenylpyruvate originating from lactic acid bacteria: Structural analysis on the substrate specificity
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2-Hydroxy acid dehydrogenases (2-HADHs) have been implicated in the synthesis of 2-hydroxy acids from 2-oxo acids that are used in wide areas of industry. D-lactate dehydrogenases (D-LDHs), a subfamily of 2-HADH, have been utilized to this purpose, yet they exhibited relatively low catalytic activity to the 2-oxo acids with large functional groups at C3. In this report, four putative 2-HADHs from Oenococcus oeni, Weissella confusa, Weissella koreensis and Pediococcus claussenii were examined for activity on phenylpyruvate (PPA), a substrate to 3-phenyllactic acid (PLA) with a C3 phenyl group. The 2-HADH from P. claussenii was found to have the highest kcat/Km on PPA with 1,348.03 s?1 mM?1 among the four enzymes with higher substrate preference for PPA than pyruvate. Sequential, structural and mutational analysis of the enzyme revealed that it belonged to the D-LDH family, and phenylalanine at the position 51 was the key residue for the PPA binding to the active site via hydrophobic interaction, whereas in the 2-HADHs from O. oeni and W. confusa the hydrophilic tyrosine undermined the interaction. Because phenyllactate is a potential precursor for pharmaceutical compounds, antibiotics and biopolymers, the enzyme could increase the efficiency of bio-production of valuable chemicals. This study suggests a structural basis for the high substrate preference of the 2-HADH, and further engineering possibilities to synthesize versatile 2-hydroxy acids.
- Lee, Hoe-Suk,Park, Jisu,Yoo, Young Je,Yeon, Young Joo
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- Stereodivergence in the Ireland-Claisen Rearrangement of α-Alkoxy Esters
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A systematic investigation into the Ireland-Claisen rearrangement of α-alkoxy esters is reported. In all cases, the use of KN(SiMe3)2 in toluene gave rearrangement products corresponding to a Z-enolate intermediate with excellent diastereoselectivity, presumably because of chelation control. On the other hand, chelation-controlled enolate formation could be overcome for most substrates through the use of lithium diisopropylamide (LDA) in tetrahydrofuran (THF).
- Podunavac, Ma?a,Lacharity, Jacob J.,Jones, Kerry E.,Zakarian, Armen
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supporting information
p. 4867 - 4870
(2018/08/24)
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- Anti-HIV medicine containing indinavir and preparation method thereof
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The invention discloses anti-HIV medicine containing indinavir and a preparation method thereof. The anti-HIV medicine containing indinavir is prepared from indinavir and pharmaceutically acceptable carriers, wherein the chemical name of indinavir is (1(1S,2R),5(S))-2,3,5-tri-deoxy-N-(2,3-dihydro-2-hydroxyl-1H-indene-1-yl)-5-[2-[[(1,1-dimethyl ethyl) amino]carbonyl]-4-(3-picolyl)-1-piperazinyl]-2-(benzyl)-D-erythro-valeramide. The process of a preparation process is simple and compact; the raw materials can be easily obtained; economic performance and environment protection are realized; the industrialization can be favorably realized; the economic technology development of the indinavir raw medicine of the anti-HIV medicine can be promoted; the dissolving-out degree of the anti-HIV medicine containing indinavir is high; the effect is ideal; the medicine is suitable for mass production.
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Paragraph 0017
(2018/08/28)
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- Enantioselective, Catalytic Vicinal Difluorination of Alkenes
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The enantioselective, catalytic vicinal difluorination of alkenes is reported by II/IIII catalysis using a novel, C2-symmetric resorcinol derivative. Catalyst turnover via in situ generation of an ArIIIIF2 species is enabled by Selectfluor oxidation and addition of an inexpensive HF–amine complex. The HF:amine ratio employed in this process provides a handle for regioselective orthogonality as a function of Br?nsted acidity. Selectivity reversal from the 1,1-difluorination pathway (geminal) to the desired 1,2-difluorination (vicinal) is disclosed (>20:1 in both directions). Validation with electron deficient styrenes facilitates generation of chiral bioisosteres of the venerable CF3 unit that is pervasive in drug discovery (20 examples, up to 94:06 e.r.). An achiral variant of the reaction is also presented using p-TolI (up to >95 % yield).
- Scheidt, Felix,Sch?fer, Michael,Sarie, Jér?me C.,Daniliuc, Constantin G.,Molloy, John J.,Gilmour, Ryan
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supporting information
p. 16431 - 16435
(2018/11/23)
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- Highly Efficient Deracemization of Racemic 2-Hydroxy Acids in a Three-Enzyme Co-Expression System Using a Novel Ketoacid Reductase
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Enantiopure 2-hydroxy acids (2-HAs) are important intermediates for the synthesis of pharmaceuticals and fine chemicals. Deracemization of racemic 2-HAs into the corresponding single enantiomers represents an economical and highly efficient approach for synthesizing chiral 2-HAs in industry. In this work, a novel ketoacid reductase from Leuconostoc lactis (LlKAR) with higher activity and substrate tolerance towards aromatic α-ketoacids was discovered by genome mining, and then its enzymatic properties were characterized. Accordingly, an engineered Escherichia coli (HADH-LlKAR-GDH) co-expressing 2-hydroxyacid dehydrogenase, LlKAR, and glucose dehydrogenase was constructed for efficient deracemization of racemic 2-HAs. Most of the racemic 2-HAs were deracemized to their (R)-isomers at high yields and enantiomeric purity. In the case of racemic 2-chloromandelic acid, as much as 300 mM of substrate was completely transformed into the optically pure (R)-2-chloromandelic acid (> 99% enantiomeric excess) with a high productivity of 83.8 g L?1 day?1 without addition of exogenous cofactor, which make this novel whole-cell biocatalyst more promising and competitive in practical application.
- Xue, Ya-Ping,Wang, Chuang,Wang, Di-Chen,Liu, Zhi-Qiang,Zheng, Yu-Guo
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- Preparation method of chiral phenyllactic acid
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The invention relates to a preparation method of chiral phenyllactic acid. The preparation method comprises the steps: salifying (S)-phenethylamine serving as a resolving agent and DL-phenyllactic acid in a specific solvent, and carrying out recrystallization to obtain (S)-phenethylamine-D-phenyl lactate; salifying (R)-phenethylamine serving as a resolving agent and DL-phenyllactic acid in a specific solvent, and carrying out recrystallization to obtain (R)-phenethylamine-L-phenyl lactate; and carrying out acid dissociation to prepare the chiral phenyllactic acid. Compared with the prior art,the preparation method has the advantages that the adopted resolving agent is cheap, available and easy to recover, and the preparation method is suitable for industrial production.
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Paragraph 0044-0046
(2018/09/29)
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- An Atropos Biphenyl Bisphosphine Ligand with 2,2′-tert-Butylmethylphosphino Groups for the Rhodium-Catalyzed Asymmetric Hydrogenation of Enol Esters
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This is an update of our previous work concerning the development of Atropos biphenyl bisphosphine ligands. An unexpected Atropos structural property was confirmed by single crystal X-ray diffraction and this result is consistent with the computational calculations described in our previous work. This P-stereogenic bisphosphine ligand possessing a biphenyl backbone and 2,2′-tert-butylmethylphosphino groups has been applied to the Rh-catalyzed asymmetric hydrogenation of enol esters, which has not been widely studied and can be used for the synthesis of several important bioactive compounds. Although there is room for further improvement in enantioselectivity, the results reported herein provide a further understanding of such types of ligands. (Figure presented.).
- Jia, Jia,Fan, Dongyang,Zhang, Jian,Zhang, Zhenfeng,Zhang, Wanbin
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p. 3793 - 3800
(2018/09/20)
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- Readily Accessible 1,2-Amino Ether Ligands for Enantioselective Intramolecular Carbolithiation
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A new class of chiral 1,2-amino ether ligands, readily accessible from naturally occurring α-amino- or α-hydroxy acids, was found to provide high levels of both conversion and stereocontrol (up to 95:5 er) in intramolecular carbolithiation reactions, outperforming the benchmark ligand (?)-sparteine. The ligand could be used in a substoichiometric amount (0.25 equiv) without significant loss of enantioselectivity.
- Guyon, Hélène,Boussonnière, Anne,Castanet, Anne-Sophie
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p. 4949 - 4957
(2017/05/12)
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- Alternating Sequence Controlled Copolymer Synthesis of α-Hydroxy Acids via Syndioselective Ring-Opening Polymerization of O-Carboxyanhydrides Using Zirconium/Hafnium Alkoxide Initiators
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The ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs) can give diverse poly(α-hydroxy acid)s (PAHAs) with different functional groups because of easy modification of the side group of OCAs, which can extend applications of PAHAs widely. The stereoselective polymerization of O-carboxyanhydrides and further sequence controlled alternating copolymerization of OCAs were still big challenges until now for lack of suitable catalysts/initiators. In this work, a highly syndioselective ROP of OCAs system as the first stereoselective example in this area is reported using zirconium/hafnium alkoxides as initiators with the highest Pr value up to 0.95. Furthermore, these initiators were successfully applied in the precisely alternating sequence controlled copolymerization of PheOCA and Tyr(Bn)OCA, and alternating copolymerization of LacOCA and PheOCA was also achieved.
- Sun, Yangyang,Jia, Zhaowei,Chen, Changjuan,Cong, Yong,Mao, Xiaoyang,Wu, Jincai
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supporting information
p. 10723 - 10732
(2017/08/15)
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- Investigating Substrate Scope and Enantioselectivity of a Defluorinase by a Stereochemical Probe
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The possibility of a double Walden inversion mechanism of the fluoracetate dehalogenase FAcD (RPA1163) has been studied by subjecting rac-2-fluoro-2-phenyl acetic acid to the defluorination process. This stereochemical probe led to inversion of configuration in a kinetic resolution with an extremely high selectivity factor (E > 500), showing that the classical mechanism involving SN2 reaction by Asp110 pertains. The high preference for the (S)-substrate is of synthetic value. Wide substrate scope of RPA1163 in such hydrolytic kinetic resolutions can be expected because the reaction of the even more sterically demanding rac-2-fluoro-2-benzyl acetic acid proceeded similarly. Substrate acceptance and stereoselectivity were explained by extensive molecular modeling (MM) and molecular dynamics (MD) computations. These computations were also applied to fluoroacetic acid itself, leading to further insights.
- Wang, Jian-Bo,Ilie, Adriana,Yuan, Shuguang,Reetz, Manfred T.
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p. 11241 - 11247
(2017/08/21)
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- Solvent-induced chirality switching in the enantioseparation of regioisomeric hydroxyphenylpropionic acids via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol
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The enantioseparation of three hydroxyphenylpropionic acid isomers via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol has been demonstrated. The racemates of all three acid isomers were successfully separated with high efficiency (0.56–0.84) after single crystallization. For 2-hydroxy-3-phenylpropionic acid 4, the configuration of the less-soluble salt was controlled by the crystallization solvent: the (R)-4 salt was crystallized from water, while 2-propanol afforded the (S)-4 salt. The chiral recognition mechanism of the three acids was discussed based on the crystal structures of the diastereomeric salts.
- Kodama, Koichi,Nagata, Jun,Kurozumi, Nobuhiro,Shitara, Hiroaki,Hirose, Takuji
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supporting information
p. 460 - 466
(2017/03/23)
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- α-Aminoxy Oligopeptides: Synthesis, Secondary Structure, and Cytotoxicity of a New Class of Anticancer Foldamers
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α-Aminoxy peptides are peptidomimetic foldamers with high proteolytic and conformational stability. To gain an improved synthetic access to α-aminoxy oligopeptides we used a straightforward combination of solution- and solid-phase-supported methods and obtained oligomers that showed a remarkable anticancer activity against a panel of cancer cell lines. We solved the first X-ray crystal structure of an α-aminoxy peptide with multiple turns around the helical axis. The crystal structure revealed a right-handed 28-helical conformation with precisely two residues per turn and a helical pitch of 5.8 ?. By 2D ROESY experiments, molecular dynamics simulations, and CD spectroscopy we were able to identify the 28-helix as the predominant conformation in organic solvents. In aqueous solution, the α-aminoxy peptides exist in the 28-helical conformation at acidic pH, but exhibit remarkable changes in the secondary structure with increasing pH. The most cytotoxic α-aminoxy peptides have an increased propensity to take up a 28-helical conformation in the presence of a model membrane. This indicates a correlation between the 28-helical conformation and the membranolytic activity observed in mode of action studies, thereby providing novel insights in the folding properties and the biological activity of α-aminoxy peptides.
- Diedrich, Daniela,Moita, Ana J. Rodrigues,Rüther, Anja,Frieg, Benedikt,Reiss, Guido J.,Hoeppner, Astrid,Kurz, Thomas,Gohlke, Holger,Lüdeke, Steffen,Kassack, Matthias U.,Hansen, Finn K.
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p. 17600 - 17611
(2016/11/28)
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- Asymmetric Assembly of All-Carbon Tertiary/Quaternary Nonadjacent Stereocenters through Organocatalytic Conjugate Addition of α-Cyanoacetates to a Methacrylate Equivalent
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An efficient, highly diastereo- and enantioselective assembly of acyclic carbonyl fragments possessing nonadjacent all-carbon tertiary/quaternary stereoarrays is reported based on a Br?nsted base catalyzed Michael addition/α-protonation sequence involving α-cyanoacetates and 2,4-dimethyl-4-hydroxypenten-3-one as novel methacrylate equivalent.
- Iriarte, Igor,Vera, Silvia,Badiola, Eider,Mielgo, Antonia,Oiarbide, Mikel,García, Jesús M.,Odriozola, José M.,Palomo, Claudio
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supporting information
p. 13690 - 13696
(2016/09/13)
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- An efficient enzymatic aminolysis for kinetic resolution of aromatic α-hydroxyl acid in non-aqueous media
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A new and highly efficient enzymatic aminolysis approach for kinetic resolution of aromatic α-hydroxy acid in non-aqueous media has been developed. The corresponding α-hydroxyl acid ester was employed as the substrate, and commercially available Candida antarctica lipase B is used as the biocatalyst, anhydrous ammonia is the resolving agent. Reactions can be proceeded smoothly in organic solvent at ambient temperatures. High concentration of substrate is allowed due to the application of organic media and the products are obtained in yields of up to 49% with ee values of up to 99%, and with E value of >300, representing an appealing and promising protocol for large-scale preparations.
- Chen, Shan,Liu, Fuyan,Zhang, Kuan,Huang, Hansheng,Wang, Huani,Zhou, Jiaying,Zhang, Jing,Gong, Yiwei,Zhang, Dela,Chen, Yiping,Lin, Chang,Wang, Bo
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supporting information
p. 5312 - 5314
(2016/11/16)
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- Enzymatic Resolution by a d-Lactate Oxidase Catalyzed Reaction for (S)-2-Hydroxycarboxylic Acids
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Oxidase-catalyzed kinetic resolution is important for the production of enantiopure 2-hydroxycarboxylic acids (2-HAs), which are versatile building blocks for the synthesis of many significant compounds. However, in contrast to that of (R)-2-HAs, the production of (S)-2-HA is challenging because of the lack of related oxidases. Herein, suitable enzymes were screened systematically through the analysis of numerous putative d-lactate oxidase sequences and identification of several required properties. Finally, a d-lactate oxidase from Gluconobacter oxydans 621H with advantageous characteristics, such as good solubility, broad substrate spectrum, and high stereoselectivity, was selected to resolve 2-HAs into (S)-2-HAs. A variety of (S)-2-HAs was produced successfully using this d-lactate oxidase with excellent enantiomeric excess values (>99 %). The presented screening criteria and approach for target biocatalysis suggested a guideline for the production of optically active chemicals such as (S)-2-HAs.
- Sheng, Binbin,Xu, Jing,Ge, Yongsheng,Zhang, Shuo,Wang, Danqi,Gao, Chao,Ma, Cuiqing,Xu, Ping
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p. 2630 - 2633
(2016/08/30)
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- Synthesis of the 5,6-dihydroxymorpholin-3-one fragment of monanchocidin a
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Monanchocidin A is a recently isolated pentacyclic guanidinium alkaloid that contains an unusual highly oxidized morpholinone fragment. Herein we report a rapid synthesis of this heterocyclic scaffold and confirm its structure. The key reaction involves an acid promoted hemiketalization/hemiaminalization of an α-hydroxyamide and α-ketoaldehyde that proceeds with exclusive regioselectivity and high diastereoselectivity to form the natural scaffold in moderate to high yield.
- Shi, Yunlong,Pierce, Joshua G.
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supporting information
p. 968 - 971
(2015/04/13)
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- Nitrilases
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition, methods of designing new nitrilases and methods of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Paragraph 0260-0262
(2015/09/22)
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- Nitrilases, nucleic acids encoding them and methods for making and using them
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition methods of designing new nitrilases and method of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Page/Page column 63; 72; 92
(2016/01/09)
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- Chiral separation of phenyllactic acid by helical structure from spring dextrin
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We performed the enzymatic synthesis of spring dextrin (SD) with a helical conformation and investigated its chiral-recognition properties in relation to the stereoselective phenyllactic acid (PLA), using reversed-phase high-performance liquid chromatography. The effects of column temperature, buffer pH and methanol content on enantioselective separation were investigated. Baseline chromatographic separation was achieved on an Inertsil ODS-SP column using 1 % SD as the chiral mobile-phase additive. Helical structure was necessary for chiral separation of PLA, according to visible spectroscopy. Molecular dynamic simulations to predict the interactions between SD and PLA showed that van der Waals attractions played an important role in enantiomer separation.
- Xu, Jin,Xu, Xueming,Wang, Qiang,Fan, Xuerong
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p. 515 - 521
(2016/02/26)
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- Biocontrolled formal inversion or retention of L -α-amino acids to enantiopure (R)- or (S)-hydroxyacids
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Natural L-α-amino acids and L-norleucine were transformed to the corresponding α-hydroxy acids by formal biocatalytic inversion or retention of absolute configuration. The one-pot transformation was achieved by a concurrent oxidation reduction cascade in aqueous media. A representative panel of enantiopure (R)- and (S)-2-hydroxy acids possessing aliphatic, aromatic and heteroaromatic moieties were isolated in high yield (67-85 %) and enantiopure form (>99 % ee) without requiring chromatographic purification.
- Busto, Eduardo,Grischek, Barbara,Kroutil, Wolfgang,Richter, Nina
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p. 11225 - 11228,4
(2015/01/07)
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- Glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of γ-glutamyl transpeptidase for probing cysteinyl-glycine binding site
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γ-Glutamyl transpeptidase (GGT) catalyzing the cleavage of γ-glutamyl bond of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione homeostasis Defining its Cys-Gly binding site is extremely important not only in defining the physiological function of GGT, but also in designing specific and effective inhibitors for pharmaceutical purposes Here we report the synthesis and evaluation of a series of glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of human and Escherichia coli GGTs to probe the structural and stereochemical preferences in the Cys-Gly binding site Both enzymes were inhibited strongly and irreversibly by the peptidyl phosphorus esters with a good leaving group (phenoxide) Human GGT was highly selective for l-aliphatic amino acid such as l-2-aminobutyrate (l-Cys mimic) at the Cys binding site, whereas E coli GGT significantly preferred l-Phe mimic at this site The C-terminal Gly and a l-amino acid analogue at the Cys binding site were necessary for inhibition, suggesting that human GGT was highly selective for glutathione (γ-Glu-l-Cys-Gly), whereas E coli GGT are not selective for glutathione, but still retained the dipeptide (l-AA-Gly) binding site The diastereoisomers with respect to the chiral phosphorus were separated Both GGTs were inactivated by only one of the stereoisomers with the same stereochemistry at phosphorus The strict recognition of phosphorus stereochemistry gave insights into the stereochemical course of the catalyzed reaction Ion-spray mass analysis of the inhibited E coli GGT confirmed the formation of a 1:1 covalent adduct with the catalytic subunit (small subunit) with concomitant loss of phenoxide, leaving the peptidyl moiety that presumably occupies the Cys-Gly binding site The peptidyl phosphonate inhibitors are highly useful as a ligand for X-ray structural analysis of GGT for defining hitherto unidentified Cys-Gly binding site to design specific inhibitors
- Nakajima, Mado,Watanabe, Bunta,Han, Liyou,Shimizu, Bun-Ichi,Wada, Kei,Fukuyama, Keiichi,Suzuki, Hideyuki,Hiratake, Jun
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p. 1176 - 1194
(2014/02/14)
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- Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids
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An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane-water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.
- Stuhr-Hansen, Nicolai,Padrah, Shahrokh,Str?mgaard, Kristian
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supporting information
p. 4149 - 4151
(2015/02/02)
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- Synthesis and antimycobacterial activity of novel camphane-based agents
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A series of six new amidoalcohols was designed and synthesized on the base of the camphor scaffold. Natural amino acids were transformed into their α-hydroxy analogues with retention of configuration, and attached to isobornylamine. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. The activity shifts from micromolar to nanomolar inhibitory concentrations depending on the α-hydroxy acid moiety. Two of the most potent compounds exert low level of cytotoxic activity. These camphane-based amido-alcohols present promising potential lead compounds for further elaboration of antimycobacterial agents.
- Stavrakov, Georgi,Philipova, Irena,Valcheva, Violeta,Momekov, Georgi
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p. 165 - 167
(2014/01/17)
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- Increased catalyst productivity in α-hydroxy acids resolution by esterase mutation and substrate modification
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Optically pure α-hydroxy acids and their derivatives are versatile chiral building blocks in the pharmaceutical industry. In this study, the potential of a recombinant Pseudomonas putida esterase (rPPE01) for the enzymatic resolution of α-acetoxy acids was significantly improved by combinatorial engineering of both the biocatalyst and substrate. Semirational design based on homologous modeling and molecular docking provided a single-point variant, W187H, whose kcat/KM for sodium 2-acetoxy-2-(2′-chlorophenyl)acetate (Ac-CPA-Na) was increased 100-fold, from 0.0611 to 6.20 mM-1 s-1, while retaining its excellent enantioselectivity and broad substrate spectrum. Biocatalyst deactivation under the operating conditions was decreased by using the potassium salt of Ac-CPA instead of Ac-CPA-Na. With 0.5 g L-1 of lyophilized cells containing rPPE01-W187H, 500 mM (R,S)-Ac-CPA-K was selectively deacylated with 49.9% conversion within 15 h, giving satisfactory enantiomeric excesses (ee) for both the S product (>99% ee) and the remaining R substrate (98.7% ee). Consequently, the amount of (S)-2-hydroxy-2-(2′-chlorophenyl)acetate prepared per unit weight of lyophilized cells was improved by a factor of 18.9 compared with the original productivity of the wild-type esterase. Further enzymatic resolution of other important hydroxy acids at the 100 mL scale demonstrated that the rPPE01-W187H-based bioprocess is versatile and practical for the large-scale preparation of chiral α-hydroxy acids.
- Ma, Bao-Di,Kong, Xu-Dong,Yu, Hui-Lei,Zhang, Zhi-Jun,Dou, Shuai,Xu, Yan-Peng,Ni, Yan,Xu, Jian-He
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p. 1026 - 1031
(2014/04/03)
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- Solid-phase synthesis of tetrahydropyridazinedione-constrained peptides
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The design and solid-phase synthesis of tetrahydropyridazine-3,6-dione (Tpd) peptidomimetics derived from backbone-aminated peptides is reported. The described protocol features the synthesis of chiral α-hydrazino acids suitable for chemoselective incorporation into growing peptide chains. Acid-catalyzed cyclization to form the Tpd ring during cleavage affords the target peptidomimetics in good yield and purity. The scope of Tpd incorporation is demonstrated through the synthesis of constrained peptides featuring nucleophilic/electrophilic side chains and sterically encumbered α-substituted hydrazino acid residues. (Chemical Equation Presented).
- Kang, Chang Won,Ranatunga, Sujeewa,Sarnowski, Matthew P.,Del Valle, Juan R.
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supporting information
p. 5434 - 5437
(2015/02/19)
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- Optical control of enzyme enantioselectivity in solid phase
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A lipase was immobilized on transparent agarose microspheres and genetically engineered to specifically anchor photochromic molecules into its catalytic site. Several combinations of azobenzene and spiropyran groups were conjugated to cysteines introduced at different positions near the active center. Light modulated the catalytic properties of the resulting solid bioconjugates, and such modulation depended on both the nature of the photochromic compound and the anchoring position. Covalent anchoring of azobenzene derivatives to the residue 295 of the lipase 2 from Bacillus thermocathenolatus triggered lipase preference for the S isomer under UV light, whereas visible light promoted preference for the R isomer. Molecular dynamics simulations indicate that conjugating photochromic compounds into the catalytic cavity allows manipulating the steric hindrance and binding energy of the substrates, leading to an enantioselective molecular fit in certain cases. Using this approach, we report for the first time the control of enzyme properties using light in the solid phase.
- Bautista-Barrufet, Antoni,Lopez-Gallego, Fernando,Rojas-Cervellera, Victor,Rovira, Carme,Pericas, Miquel A.,Guisan, Jose M.,Gorostiza, Pau
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p. 1004 - 1009
(2014/04/03)
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- Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids
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An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane-water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.
- Stuhr-Hansen, Nicolai,Padrah, Shahrokh,Str?mgaard, Kristian
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supporting information
p. 4149 - 4151
(2014/07/22)
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- Preparation and evaluation at the delta opioid receptor of a series of linear Leu-enkephalin analogues obtained by systematic replacement of the amides
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Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds.
- Rochon, Kristina,Proteau-Gagne, Arnaud,Bourassa, Philippe,Nadon, Jean-Francois,Coite, Jerome,Bournival, Veronique,Gobeil, Fernand,Guerin, Brigitte,Dory, Yves L.,Gendron, Louis
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p. 1204 - 1216
(2013/09/23)
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- Enantioselective reduction of 3-aryl-2-oxo-propanoic acids: A comparison of enzymatic and transition-metal-catalyzed methods
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Phenyllactic acids are important constituents of depsipeptides, which are a large class of natural products expressing a wide range of biological activities. Despite there being several methods for the enantioselective synthesis of α-hydroxy acids, almost no studies are available addressing the substrate selectivity of transition-metal and enzyme-catalyzed methods for the preparation of substituted phenyllactic or more general aryllactic acids. We report herein comparative results for Rh-DiPAMP (DiPAMP = 1,2-ethandiylbis[(o- methoxyphenyl)phenylphosphane]) and lactate dehydrogenase catalyzed enantioselective reductions of several 3-aryl-2-oxopropanoic acids. Phenyllactic acids are important constituents of depsipeptides, which are a large class of natural products expressing a wide range of biological activities. A comparative study of transition-metal and lactate dehydrogenase catalyzed enantioselective reductions of several 3-aryl-2-oxopropanoic acids as valuable sources for enantiomerically pure phenyllactic acids is described. Copyright
- Luettenberg, Sebastian,Ta, Tien Dat,Von Der Heyden, Jan,Scherkenbeck, Juergen
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p. 1824 - 1830
(2013/06/04)
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- One-pot, single-step deracemization of 2-hydroxyacids by tandem biocatalytic oxidation and reduction
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A facile and efficient one-pot, single-step method for deracemizing a broad range of 2-hydroxyacids to (R)-2-hydroxyacids was established by combination of resting cells of an (S)-hydroxyacid dehydrogenase-producing microorganism and an (R)-ketoacid reductase-producing microorganism.
- Xue, Ya-Ping,Zheng, Yu-Guo,Zhang, Ya-Qin,Sun, Jing-Lei,Liu, Zhi-Qiang,Shen, Yin-Chu
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supporting information
p. 10706 - 10708
(2013/11/06)
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- Continuous multiple liquid-liquid separation: Diazotization of amino acids in flow
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A second-generation laboratory-scale, modular liquid-liquid separation device based on computer-controlled high-pressure pumps and a high-resolution digital camera has been invented. The diazotization of amino acids to produce valuable chiral hydroxyacids is demonstrated in flow for the first time. The use of a triple-separator system in conjuction with the developed diazotization process allows the safe and efficient production and automated isolation of multigram quantities of valuable chiral hydroxyacids.
- Hu, Dennis X.,O'Brien, Matthew,Ley, Steven V.
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supporting information; experimental part
p. 4246 - 4249
(2012/10/08)
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- Anthelmintic PF1022A: Stepwise solid-phase synthesis of a cyclodepsipeptide containing N-methyl amino acids
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Cyclodepsipeptides of the enniation-, PF1022-, and verticilide-family represent a diverse class of highly interesting natural products with respect to their manifold biological activities. However, until now no stepwise solid-phase synthesis has been accomplished due to the difficult combination of N-methyl amino acids and hydroxycarboxylic acids. We report here the first stepwise solid-phase synthesis of the anthelmintic cyclooctadepsipeptide PF1022A based on an Fmoc/THP-ether protecting group strategy on Wang-resin. The standard conditions of our synthesis allow an unproblematic adaption to an automated peptide synthesizer.
- Lüttenberg, Sebastian,Sondermann, Frank,Scherkenbeck, Jürgen
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scheme or table
p. 2068 - 2073
(2012/03/27)
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- Synthesis, characterization and activity of new phosphonate dipeptides as potential inhibitors of VanX
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VanX, a Zn(II)-dependent D-ala-D-ala dipeptidase, is essential for vancomycin resistance in Enterococcus faecium. The enzymatic activity of VanX was previously found to be inhibited competitively by 2-{[(1-aminoethyl) (hydroxy) phosphoryl]oxy} propanoic acid (1B). Here we report the synthesis and characterization of seven phosphonate dipeptide analogs of D-ala-D-ala with various substituent, the activity evaluation indicated that six of these phosphonate analogs inhibit VanX with IC50 of 0.48-8.21 mM. These data revealed a structure-activity relationship which is that the large substituent group on β-carbon resulted in low binding affinity of the phonphonate analog to VanX. This information will be helpful to guide the design and synthesis of the tightly-binding inhibitors for VanX.
- Jia, Chao,Yang, Ke-Wu,Liu, Cheng-Cheng,Feng, Lei,Xiao, Jian-Min,Zhou, Li-Sheng,Zhang, Yi-Lin
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supporting information; experimental part
p. 482 - 484
(2012/03/11)
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- Enantioseparation of typical pesticides using cellulose carbamate stationary phases by capillary liquid chromatography
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Cellulose-tris(3,5-dimethylphenylcarbamate) was initially synthesized as the chiral selector, then stable coated and bonded chiral stationary phases were prepared, respectively, using aminopropyl-functionalized silica gel as the support media. The prepared stationary phases were used for micro-column chiral separation by self-installed capillary high performance liquid chromatography system. Eighteen kind of chiral compounds including some typical pesticides were tested on both prepared chiral stationary phases and different chromatographic parameters such as resolution and retention time were comparatively investigated.
- Bai, Lian-Yang,Zhang, Yu-Ping,Deng, Pu-Hong,Zhang, Yi-Jun,Chen, Jun
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experimental part
p. 4917 - 4922
(2012/10/08)
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- Cyclic depsipeptides, grassypeptolides D and e and Ibu- epidemethoxylyngbyastatin 3, from a Red Sea Leptolyngbya cyanobacterium
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Two new grassypeptolides and a lyngbyastatin analogue, together with the known dolastatin 12, have been isolated from field collections and laboratory cultures of the marine cyanobacterium Leptolyngbya sp. collected from the SS Thistlegorm shipwreck in the Red Sea. The overall stereostructures of grassypeptolides D (1) and E (2) and Ibu-epidemethoxylyngbyastatin 3 (3) were determined by a combination of 1D and 2D NMR experiments, MS analysis, Marfey's methodology, and HPLC-MS. Compounds 1 and 2 contain 2-methyl-3-aminobutyric acid and 2-aminobutyric acid, while biosynthetically distinct 3 contains 3-amino-2-methylhexanoic acid and the β-keto amino acid 4-amino-2,2-dimethyl-3-oxopentanoic acid (Ibu). Grassypeptolides D (1) and E (2) showed significant cytotoxicity to HeLa (IC50 = 335 and 192 nM, respectively) and mouse neuro-2a blastoma cells (IC50 = 599 and 407 nM, respectively), in contrast to Ibu-epidemethoxylyngbyastatin 3 (neuro-2a cells, IC50 > 10 μM) and dolastatin 12 (neuro-2a cells, IC 50 > 1 μM).
- Thornburg, Christopher C.,Thimmaiah, Muralidhara,Shaala, Lamiaa A.,Hau, Andrew M.,Malmo, Jay M.,Ishmael, Jane E.,Youssef, Diaa T. A.,McPhail, Kerry L.
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experimental part
p. 1677 - 1685
(2011/11/04)
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- Bioactive compounds from the scale insect pathogenic fungus conoideocrella tenuis BCC 18627
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A new cyclohexadepsipeptide, conoideocrellide A (1), its linear derivatives, conoideocrellides B-D (2-4), three new hopane triterpenoids (5-7), two new bioxanthracenes (9 and 10), and a new isocoumarin glycoside (13) were isolated from the scale insect pathogenic fungus Conoideocrella tenuis BCC 18627. Biological activities of the new compounds were evaluated.
- Isaka, Masahiko,Palasarn, Somporn,Supothina, Sumalee,Komwijit, Somjit,Luangsa-Ard, J. Jennifer
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experimental part
p. 782 - 789
(2011/06/21)
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- Concise, protecting group free total syntheses of (+)-sattabacin and (+)-4-hydroxysattabacin
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The first asymmetric total syntheses of the antiviral natural products (+)-sattabacin and (+)-4-hydroxysattabacin are reported. Both total syntheses are remarkably concise and were completed without the use of protecting groups. These syntheses allowed the unambiguous assignment of the absolute configuration of both natural products. The syntheses of these natural products, which exhibit marked antiviral activity, are readily amenable to the preparation of structural analogs and progress in this regard is also reported.
- Aronoff, Matthew R.,Bourjaily, Neil A.,Miller, Kenneth A.
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scheme or table
p. 6375 - 6377
(2011/01/03)
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