共查询到20条相似文献,搜索用时 15 毫秒
1.
Dr. Marta Pelay‐Gimeno Dr. Tanja Bange Dr. Sven Hennig Prof. Dr. Tom N. Grossmann 《Angewandte Chemie (International ed. in English)》2018,57(35):11164-11170
Increased tolerance of enzymes towards thermal and chemical stress is required for many applications and can be achieved by macrocyclization of the enzyme resulting in the stabilizing of its tertiary structure. Thus far, macrocyclization approaches utilize a very limited structural diversity, which complicates the design process. Herein, we report an approach that enables cyclization through the installation of modular crosslinks into native proteins composed entirely of proteinogenic amino acids. Our stabilization procedure involves the introduction of three surface‐exposed cysteine residues, which are reacted with a triselectrophile, resulting in the in situ cyclization of the protein (INCYPRO). A bicyclic version of sortase A was designed that exhibits increased tolerance towards thermal as well as chemical denaturation, and proved to be efficient in protein labeling under denaturing conditions. In addition, we applied INCYPRO to the KIX domain, resulting in up to 24 °C increased thermal stability. 相似文献
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Linping Liao Dr. Jingjing Zhou Dr. Zhengshuang Xu Prof. Dr. Tao Ye 《Angewandte Chemie (International ed. in English)》2016,55(42):13263-13266
Nannocystin A, a structurally unique 21‐membered macrocyclic depsipeptide with low nanomolar inhibitory activity against elongation factor 1A, was synthesized according to a strategy involving the vinylogous Mukaiyama aldol reaction, Sharpless epoxidation, olefin metathesis, the Mitsunobu reaction, and a palladium‐catalyzed intramolecular Suzuki coupling of a highly complex cyclization substrate. The overall synthesis is efficient and paves the way for preparation of analogues for drug development efforts. 相似文献
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Guangri Yu Prof. Dr. Byunghyuck Jung Prof. Dr. Hee‐Seung Lee Prof. Dr. Sung Ho Kang 《Angewandte Chemie (International ed. in English)》2016,55(7):2573-2576
The first total synthesis of inostamycin A is described. With efficient and stereoselective synthetic routes to aldehyde 3 and ketone 4 developed through asymmetric aldol reactions, addition reactions and reduction, and with chiral building blocks, the two large fragments were coupled with remarkable anti stereoselectivity and efficiency by aldol condensation. The coupling reaction provided the complete carbon skeleton with all the requisite functional groups and stereogenic centers for inostamycin A. The two quaternary carbons at C20 and C16 of ketone 4 were elaborated in a highly stereocontrolled manner by addition reactions of the transmetallated 5 to ethyl ketone 6 and the transmetallated 7 to methyl ketone 8 , respectively, in which the use of LaCl3 for transmetallation was critical for high coupling efficiency. 相似文献
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Lactacystin and salinosporamide A are fascinating molecules with regard to both their chemical structures and biological activities. These naturally occurring compounds are potent and selective proteasome inhibitors. The molecular structures are characterized by their densely functionalized γ‐lactam cores. The structure and biological properties of these two compounds are attracting the attention of many chemists as challenging synthetic targets. We discuss their synthetic strategies in this review. 相似文献
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Dr. Amit B. Pawar Prof. Dr. Kavirayani R. Prasad 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(47):15202-15206
A formal total synthesis of the 20‐membered marine macrolide, palmerolide A from chiral pool tartaric acid is described. Elaboration of a γ‐hydroxy amide, which is derived from the desymmetrization of tartaric acid amide, and Boord olefination are the pivotal reactions employed for the synthesis of the chiral building blocks, and Stille coupling and ring‐closing metathesis (RCM) are used to assemble the macrolactone. 相似文献
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Ming Gao Ye‐Cheng Wang Kai‐Rui Yang Dr. Wei He Prof. Dr. Xiao‐Liang Yang Prof. Dr. Zhu‐Jun Yao 《Angewandte Chemie (International ed. in English)》2018,57(40):13313-13318
The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.01,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective LaIII‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI2‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A. 相似文献
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Stanley Chang Soo Hur Prof. Robert Britton 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(46):16646-16653
The total synthesis of the marine fungus‐derived natural product ascospiroketal is described. This concise synthesis relies on a unique AgI‐promoted tandem cascade cyclization that provides direct access to the correctly configured tricyclic core of the natural product from a linear precursor. The synthesis of candidate stereostructures of ascospiroketal A allowed for the confident assignment of both the relative and absolute stereochemistry of this unusual octaketide. 相似文献
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Dr. Loïc Tomas Dr. Gustav Boije af Gennäs Dr. Marie Aude Hiebel Dr. Peter Hampson Dr. David Gueyrard Dr. Béatrice Pelotier Prof. Jari Yli‐Kauhaluoma Prof. Olivier Piva Prof. Janet M. Lord Prof. Peter G. Goekjian 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(24):7452-7466
The total synthesis of bistramide A and its 36(Z),39(S) and 36(Z),39(R) isomers shows that these compounds have different effects on cell division and apoptosis. The synthesis relies on a novel enol ether‐forming reaction for the spiroketal fragment, a kinetic oxa‐Michael cyclization reaction for the tetrahydropyran fragment, and an asymmetric crotonylation reaction for the amino acid fragment. Preliminary biological studies show a distinct pattern of influence of each of the three compounds on cell division, differentiation, and apoptosis in HL‐60 cells, thus suggesting that these effects are independent activities of the natural product. 相似文献
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Kazuhiro Tsuna Naoyoshi Noguchi Prof. Dr. Masahisa Nakada 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(17):5476-5486
The enantioselective total synthesis of (+)‐ophiobolin A is described. This total synthesis features the construction of the spiro CD ring of (+)‐ophiobolin A through a stereoselective intramolecular Hosomi–Sakurai cyclization reaction, the joining of the A ring to the CD ring by using a reaction reported by Utimoto, and the construction of the ophiobolin eight‐membered carbocyclic ring through ring‐closing metathesis (RCM), which was performed for the first time in this study. This successful RCM reaction required the use of a substrate that contained either a benzyloxy or a methoxymethoxy group at the C5 position and either an isopropenyl group or its hydroxylated form at the C6 position. 相似文献
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Ross S. Harvey Emily G. Mackay Lukas Roger Prof. Michael N. Paddon‐Row Prof. Michael S. Sherburn Dr. Andrew L. Lawrence 《Angewandte Chemie (International ed. in English)》2015,54(6):1795-1798
The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5‐diaryl‐3,4‐dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels–Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6‐31G(d) and M06‐2X/6‐31G(d) model chemistries. 相似文献
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Daohong Liao Shaoqiang Yang Jianyu Wang Jian Zhang Benke Hong Fan Wu Prof. Dr. Xiaoguang Lei 《Angewandte Chemie (International ed. in English)》2016,55(13):4291-4295
The increase and spread of Gram‐negative bacteria that resistant are to almost all currently available β‐lactam antibiotics is a major global health problem. The primary cause for drug resistance is the acquisition of metallo‐β‐lactamases such as metallo‐β‐lactamase‐1 (NDM‐1). The fungal natural product aspergillomarasmine A (AMA), a fungal natural product, is an inhibitor of NDM‐1 and has shown promising in vivo therapeutic potential in a mouse model infected with NDM‐1‐expressing Gram‐negative bacteria. The first total synthesis and stereochemical configuration reassignment of aspergillomarasmine A is reported. The synthesis highlights a flexible route and an effective strategy to achieve the required oxidation state at a late stage. This modular route is amenable to the efficient preparation of analogues for the development of metallo‐β‐lactamase inhibitors to potentiate β‐lactam antibiotics. 相似文献
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Total Chemical Synthesis and Biological Activities of Glycosylated and Non‐Glycosylated Forms of the Chemokines CCL1 and Ser‐CCL1 下载免费PDF全文
Prof. Dr. Ryo Okamoto Dr. Kalyaneswar Mandal Dr. Morris Ling Prof. Dr. Andrew D. Luster Prof. Dr. Yasuhiro Kajihara Prof. Dr. Stephen B. H. Kent 《Angewandte Chemie (International ed. in English)》2014,53(20):5188-5193
CCL1 is a naturally glycosylated chemokine protein that is secreted by activated T‐cells and acts as a chemoattractant for monocytes. 1 Originally, CCL1 was identified as a 73 amino acid protein having one N‐glycosylation site, 1 and a variant 74 residue non‐glycosylated form, Ser‐CCL1, has also been described. 2 There are no systematic studies of the effect of glycosylation on the biological activities of either CCL1 or Ser‐CCL1. Here we report the total chemical syntheses of both N‐glycosylated and non‐glycosylated forms of (Ser‐)CCL1, by convergent native chemical ligation. We used an N‐glycan isolated from hen egg yolk together with the Nbz linker for Fmoc chemistry solid phase synthesis of the glycopeptide‐αthioester building block. 3 Chemotaxis assays of these glycoproteins and the corresponding non‐glycosylated proteins were carried out. The results were correlated with the chemical structures of the (glyco)protein molecules. To the best of our knowledge, these are the first investigations of the effect of glycosylation on the chemotactic activity of the chemokine (Ser‐)CCL1 using homogeneous N‐glycosylated protein molecules of defined covalent structure. 相似文献
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Dr. Masahito Yoshida Dr. Koya Saito Dr. Hikaru Kato Prof. Dr. Sachiko Tsukamoto Prof. Dr. Takayuki Doi 《Angewandte Chemie (International ed. in English)》2018,57(18):5147-5150
The total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. AuCl3‐catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner–Wadsworth–Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid‐labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinol A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53–Hdm2 interaction. 相似文献
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Stefan A. Ruider Tobias Sandmeier Prof. Dr. Erick M. Carreira 《Angewandte Chemie (International ed. in English)》2015,54(8):2378-2382
The first total synthesis of the marine polyketide (±)‐hippolachnin A has been achieved in nine linear steps and an overall yield of 9 %. Rapid access to the oxacyclobutapentalene core structure was secured by strategic application of an ene cyclization. 相似文献
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Dr. Jenny Barbier Dr. Jens Wegner Dr. Stefan Benson Dr. Juliane Gentzsch Prof. Dr. Thomas Pietschmann Prof. Dr. Andreas Kirschning 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(29):9083-9090
The total synthesis of 16 new ion channel inhibitors derived from noricumazole A, a secondary metabolite from the myxobacterium Sorangium cellulosum, is reported. Particular focus of library design is put on stereochemical permutations in the central region (C9 and C11), the oxazole moiety and the side chain at C4 of the isochromanone moiety. Noricumazole A and all new noricumazole derivatives were tested in an assay system with inhibitory effect on the hepatitis C virus (HCV) life cycle. Most of them are moderate to strong HCV inhibitors (350 nM –6 nM ) but also exert pronounced cytotoxicity. In contrast, the thiazole analogue of noricumazole A is a strong HCV inhibitor with only moderate cytotoxic property. It may become a lead structure with a good therapeutic index (CC50/IC50) of greater than 10. 相似文献
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Enzyme‐Mediated,Site‐Specific Protein Coupling Strategies for Surface‐Based Binding Assays 下载免费PDF全文
Dr. Wolfgang Ott Ellis Durner Prof. Dr. Hermann E. Gaub 《Angewandte Chemie (International ed. in English)》2018,57(39):12666-12669
Covalent surface immobilization of proteins for binding assays is typically performed non‐specifically via lysine residues. However, receptors that either have lysines near their binding pockets, or whose presence at the sensor surface is electrostatically disfavoured, can be hard to probe. To overcome these limitations and to improve the homogeneity of surface functionalization, we adapted and optimized three different enzymatic coupling strategies (4′‐phosphopantetheinyl transferase, sortase A, and asparaginyl endopeptidase) for biolayer interferometry surface modification. All of these enzymes can be used to site‐specifically and covalently ligate proteins of interest via short recognition sequences. The enzymes function under mild conditions and thus immobilization does not affect the receptors’ functionality. We successfully employed this enzymatic surface functionalization approach to study the binding kinetics of two different receptor–ligand pairs. 相似文献
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Michael A. Schafroth Giuseppe Zuccarello Simon Krautwald Dr. David Sarlah Prof. Dr. Erick M. Carreira 《Angewandte Chemie (International ed. in English)》2014,53(50):13898-13901
All four stereoisomers of Δ9‐tetrahydrocannabinol (Δ9‐THC) were synthesized in concise fashion using stereodivergent dual catalysis. Thus, following identical synthetic sequences and applying identical reaction conditions to the same set of starting materials, selective access to the four stereoisomers of THC was achieved in five steps. 相似文献