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1.
Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A
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Jonathan J. Mills Kaylib R. Robinson Troy E. Zehnder Prof. Joshua G. Pierce 《Angewandte Chemie (International ed. in English)》2018,57(28):8682-8686
Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4‐oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow‐up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4‐oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization. 相似文献
2.
Plant Antimicrobial Peptides Snakin‐1 and Snakin‐2: Chemical Synthesis and Insights into the Disulfide Connectivity
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Dr. Paul W. R. Harris Dr. Sung‐Hyun Yang Prof. Antonio Molina Gemma López Martin Middleditch Prof. Margaret A. Brimble 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(17):5102-5110
Antimicrobial peptides and proteins represent an important class of plant defensive compounds against pathogens and provide a rich source of lead compounds in the field of drug discovery. We describe the effective preparation of the cysteine‐rich snakin‐1 and ‐2 antimicrobial peptides by using a combination of solid‐phase synthesis and native chemical ligation. A subsequent cysteine/cystine mediated oxidative folding to form the six internal disulfide bonds concurrently gave the folded proteins in 40–50 % yield. By comparative evaluation of mass spectrometry, HPLC, biological data and trypsin digest mapping of folded synthetic snakin‐2 compared to natural snakin‐2, we demonstrated that synthetic snakin‐2 possesses full antifungal activity and displayed similar chromatographic behaviour to natural snakin‐2. Trypsin digest analysis allowed tentative assignment of three of the purported six disulfide bonds. 相似文献
3.
Shermin S. Goh Guilhem Chaubet Birgit Gockel Marie‐Caroline A. Cordonnier Hannah Baars Andrew W. Phillips Edward A. Anderson 《Angewandte Chemie (International ed. in English)》2015,54(43):12618-12621
Two enantioselective total syntheses of the nortriterpenoid natural product rubriflordilactone A are described, which use palladium‐ or cobalt‐catalyzed cyclizations to form the CDE rings, and converge on a late‐stage synthetic intermediate. These key processes are set up through the convergent coupling of a common diyne component with appropriate AB‐ring aldehydes, a strategy that sets the stage for the synthetic exploration of other members of this family of natural products. 相似文献
4.
Karen Lienkamp Dr. Gregory N. Tew Prof. 《Chemistry (Weinheim an der Bergstrasse, Germany)》2009,15(44):11784-11800
Natural macromolecules exhibit an extensive arsenal of properties, many of which have proven difficult to recapitulate in simpler synthetic systems. Over the last couple of years, foldamers have emerged as one important step toward increased functionality in synthetic systems. While the great majority of work in this area has focused on folded structures, hence the name, more recent progress has centered on polymers that mimic protein function. These efforts have resulted in the design of relatively simple macromolecules; one example are the synthetic mimics of antimicrobial peptides (SMAMPs) that capture the central physicochemical features of their natural archetypes irrespective of the specific folded form. Here we present our recent efforts to create polymers which display biological activity similar to natural proteins, including antimicrobial and cell‐penetrating peptides. 相似文献
5.
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
6.
Dipl.‐Chem. Jens Willwacher Prof. Alois Fürstner 《Angewandte Chemie (International ed. in English)》2014,53(16):4217-4221
A concise synthesis of the putative structure assigned to the highly cytotoxic marine macrolide mandelalide A ( 1 ) is disclosed. Specifically, an iridium‐catalyzed two‐directional Krische allylation and a cobalt‐catalyzed carbonylative epoxide opening served as convenient entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal‐acetylene metathesis into natural product synthesis, which is remarkable as this class of substrates was beyond reach until very recently; key to success was the use of the highly selective molybdenum alkylidyne complex 42 as the catalyst. Although the constitution and stereochemistry of the synthetic samples are unambiguous, the spectra of 1 as well as of 11‐epi‐ 1 deviate from those of the natural product, which implies a subtle but deep‐seated error in the original structure assignment. 相似文献
7.
Sepand K. Nistanaki Luke A. Boralsky Roy D. Pan Hosea M. Nelson 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(6):1738-1740
Disclosed is a five‐step synthesis of (±)‐vibralactone, a biologically active terpenoid natural product. A key photochemical valence isomerization of 3‐prenyl‐pyran‐2‐one produces both the all‐carbon quaternary stereocenter and the β‐lactone at an early stage. Cyclopropanation of the resulting bicyclic β‐lactone produces a strained housane structure that is converted to the natural product through a sequential ring expansion and reduction strategy. This concise and modular route to the natural product provides the shortest total synthesis of (±)‐vibralactone reported to date. 相似文献
8.
Total Synthesis of the Posttranslationally Modified Polyazole Peptide Antibiotic Plantazolicin A
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Hiroki Wada Dr. Huw E. L. Williams Prof. Christopher J. Moody 《Angewandte Chemie (International ed. in English)》2015,54(50):15147-15151
The power of rhodium–carbene methodology in chemistry is demonstrated by the synthesis of a structurally complex polyazole antibiotic. Plantazolicin A, a novel soil‐bacterium metabolite, comprises a linear array of 10 five‐membered rings in two pentacyclic regions that derive from ribosomal peptide synthesis followed by extensive posttranslational modification. The compound possesses potent antimicrobial activity, and is selectively active against the anthrax‐causing organism. A conceptually different synthesis of plantazolicin A is reported in which the key steps are the use of rhodium(II)‐catalyzed reactions of diazocarbonyl compounds to generate up to six of the seven oxazole rings of the antibiotic. NMR spectroscopic studies and molecular modeling reveal a likely dynamic hairpin conformation with a hinge region around the two isoleucine residues. The compound has modest activity against methicillin‐resistant Staphylococcus aureus (MRSA). 相似文献
9.
Serhii O. Kokhan Andriy V. Tymtsunik Stephan L. Grage Sergii Afonin Oleg Babii Marina Berditsch Alexander V. Strizhak Dmytro Bandak Maxim O. Platonov Igor V. Komarov Anne S. Ulrich Pavel K. Mykhailiuk 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2016,128(47):15008-15012
A conformationally restricted monofluorinated α‐amino acid, (3‐fluorobicyclo[1.1.1]pentyl)glycine (F‐Bpg), was designed as a label for the structural analysis of membrane‐bound peptides by solid‐state 19F NMR spectroscopy. The compound was synthesized and validated as a 19F label for replacing natural aliphatic α‐amino acids. Calculations suggested that F‐Bpg is similar to Leu/Ile in terms of size and lipophilicity. The 19F NMR label was incorporated into the membrane‐active antimicrobial peptide PGLa and provided information on the structure of the peptide in a lipid bilayer. 相似文献
10.
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
11.
Design,Synthesis, and Application of an Optimized Monofluorinated Aliphatic Label for Peptide Studies by Solid‐State 19F NMR Spectroscopy
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Serhii O. Kokhan Andriy V. Tymtsunik Dr. Stephan L. Grage Dr. Sergii Afonin Dr. Oleg Babii Dr. Marina Berditsch Alexander V. Strizhak Dmytro Bandak Dr. Maxim O. Platonov Prof. Igor V. Komarov Prof. Anne S. Ulrich Dr. Pavel K. Mykhailiuk 《Angewandte Chemie (International ed. in English)》2016,55(47):14788-14792
A conformationally restricted monofluorinated α‐amino acid, (3‐fluorobicyclo[1.1.1]pentyl)glycine (F‐Bpg), was designed as a label for the structural analysis of membrane‐bound peptides by solid‐state 19F NMR spectroscopy. The compound was synthesized and validated as a 19F label for replacing natural aliphatic α‐amino acids. Calculations suggested that F‐Bpg is similar to Leu/Ile in terms of size and lipophilicity. The 19F NMR label was incorporated into the membrane‐active antimicrobial peptide PGLa and provided information on the structure of the peptide in a lipid bilayer. 相似文献
12.
Stefan Fischer Nikolas Huwyler Dr. Susanne Wolfrum Prof. Dr. Erick M. Carreira 《Angewandte Chemie (International ed. in English)》2016,55(7):2555-2558
We disclose the syntheses of (+)‐bromodanicalipin A as well as (±)‐fluorodanicalipin A. The relative configuration and ground‐state conformation in solution of both molecules was secured by J‐based configuration analysis which revealed that these are identical to natural danicalipin A. Furthermore, preliminary toxicological investigations suggest that the adverse effect of danicalipin A may be due to the lipophilicity of the halogens. 相似文献
13.
《Journal of heterocyclic chemistry》2017,54(2):1619-1624
A series of 1,2‐dihydroquinoxaline‐3‐yl‐3‐substitutedphenyl‐1H‐pyrazole‐4‐carbaldehyde were synthesized and evaluated for their antimicrobial activity against two Gram‐positive and two Gram‐negative organisms and two fungal organisms. The study has shown that pyrazole‐4‐carbaldehyde‐incorporated quinoxaline was essential for activity. Among the compounds, 5a , 5c , 5d had shown significant activity against all selected strains when compared with control. These compounds may prove useful as antimicrobial agents. 相似文献
14.
Prof. Dr. Hak Joong Kim Dr. Sei‐hyun Choi Byung‐sun Jeon Dr. Namho Kim Prof. Dr. Rongson Pongdee Dr. Qingquan Wu Prof. Dr. Hung‐wen Liu 《Angewandte Chemie (International ed. in English)》2014,53(49):13553-13557
Following the biosynthesis of polyketide backbones by polyketide synthases (PKSs), post‐PKS modifications result in a significantly elevated level of structural complexity that renders the chemical synthesis of these natural products challenging. We report herein a total synthesis of the widely used polyketide insecticide spinosyn A by exploiting the prowess of both chemical and enzymatic methods. As more polyketide biosynthetic pathways are characterized, this chemoenzymatic approach is expected to become readily adaptable to streamlining the synthesis of other complex polyketides with more elaborate post‐PKS modifications. 相似文献
15.
Hiu C. Lam Justin T. J. Spence Dr. Jonathan H. George 《Angewandte Chemie (International ed. in English)》2016,55(35):10368-10371
Hyperjapones A–E and hyperjaponols A–C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjapones A–E using a biomimetic, oxidative hetero‐Diels–Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjapone A is proposed to be the biosynthetic precursor of hyperjaponol C through a sequence of: 1) epoxidation; 2) acid‐catalyzed epoxide ring‐opening; and 3) a concerted, asynchronous alkene cyclization and 1,2‐alkyl shift of a tertiary carbocation. Chemical mimicry of this proposed biosynthetic sequence allowed a concise total synthesis of hyperjaponol C to be completed in which six carbon–carbon bonds, six stereocenters, and three rings were constructed in just four steps. 相似文献
16.
Gold‐Catalyzed Cyclization Leads to a Bridged Tetracyclic Indolenine that Represses β‐Lactam Resistance
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Dr. Wenqing Xu Dr. Wei Wang Prof. Dr. Xiang Wang 《Angewandte Chemie (International ed. in English)》2015,54(33):9546-9549
A gold‐catalyzed desilylative cyclization was developed for facile synthesis of bridged tetracyclic indolenines, a common motif in many natural indole alkaloids. An antimicrobial screen of the cyclization products identified one compound which selectively potentiates β‐lactam antibiotics in methicillin‐resistant S. aureus (MRSA), and re‐sensitizes a variety of MRSA strains to β‐lactams. 相似文献
17.
Mahesh B. Muluk Pramod S. Phatak Shriram B. Pawar Sambhaji T. Dhumal Naziya N. M. A. Rehman Prashant P. Dixit Prafulla B. Choudhari Kishan P. Haval 《中国化学会会志》2019,66(11):1507-1517
A series of novel substituted (E)‐N′‐benzylidene‐4‐methyl‐2‐(2‐propylpyridin‐4‐yl)thiazole‐5‐carbohydrazide derivatives ( 6a‐l ) have been synthesized by following the multistep synthetic route starting from prothionamide. The resulting compounds were characterized via 1H, 13C NMR, and HRMS spectral data. The synthesized carbohydrazides were evaluated for their in vitro antimicrobial and antioxidant activities. Tested molecules have displayed moderate to good growth inhibition activity. Among the screened compounds, 6b , 6e , 6j, and 6k are found to be the more promising antimicrobial agents. A 2,2‐diphenyl‐1‐picrylhydrazyl assay was used to test the antioxidant activity of the carbohydrazides. The carbohydrazide derivatives 6b and 6i have shown better free‐radical scavenging ability than the other investigated compounds. 相似文献
18.
Keisuke Sakurai Prof. Dr. Makoto Sasaki Prof. Dr. Haruhiko Fuwa 《Angewandte Chemie (International ed. in English)》2018,57(18):5143-5146
Total synthesis of (?)‐enigmazole A, a marine macrolide natural product with cytotoxic activity, has been accomplished. The tetrahydropyran moiety was constructed by means of a domino olefin cross‐metathesis/intramolecular oxa‐Michael addition of a δ‐hydroxy olefin. After coupling of advanced intermediates, the macrocycle was formed through gold‐catalyzed rearrangement of a propargylic benzoate, followed by ring‐closing metathesis of the resultant α,β‐unsaturated ketone. 相似文献
19.
A Concise and Versatile Synthesis of Alkaloids from Kopsia tenuis: Total Synthesis of (±)‐Lundurine A and B
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Prof. Shigeru Arai Masaya Nakajima Prof. Atsushi Nishida 《Angewandte Chemie (International ed. in English)》2014,53(22):5569-5572
A total synthesis of (±)‐lundurines A and B is described. These natural products have a unique hexacyclic skeleton which includes a cyclopropane‐fused indoline. A stereospecific construction of the pentasubstituted cyclopropane core was achieved, by radical cyclization using SmI2, with perfect stereoselectivity. Cyclizations to give seven‐ and five‐membered heterocycles, under palladium and ruthenium catalysis, respectively, accomplished the total syntheses. The late‐stage construction of the F ring by ring‐closing metathesis enabled access to the title compounds from a spiroindoline intermediate which is a common structure of other kopsia alkaloids. 相似文献
20.
《Journal of heterocyclic chemistry》2017,54(2):1590-1597
A new series of 2‐aryl‐5‐((2‐arylthiazol‐4‐yl)methyl)‐1,3,4‐oxadiazole derivatives was synthesized by condensation of 2‐(2‐substituted thiazol‐4‐yl)acetohydrazide with aryl aldehydes followed by oxidative cyclocondensation using iodobenzene diacetate. The structure of synthesized compounds was characterized by IR, NMR, and mass analysis. All the newly synthesized compounds were evaluated for their in vitro antimicrobial activity. Some of the compounds showed moderate antimicrobial activity. 相似文献