Synthesis of Enopeptin B from <i>Streptomyces</i> sp RK‐1051

Schmidt, Ulrich; Neumann, Karin; Schumacher, Andreas; Weinbrenner, Steffen

doi:10.1002/anie.199711101

Cited by 16 publications

(15 citation statements)

References 24 publications

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“…The ADEP analogues used in this study were accessed by one of two synthetic routes. The first involves a solution-phase sequence developed by Schmidt (Scheme ), , which employs standard peptide coupling reagents and protecting groups, while the second route, recently developed by our group, involves a solid-phase peptide synthesis (SPPS)/dysprosium(III) triflate-mediated macrolactonization sequence (Scheme ). For the first approach, tripeptide ( 12a and 12b ) and dipeptide/depsipeptide ( 13a – d ) , fragments were initially coupled to give linear pentapeptide/depsipeptide intermediates ( 14a – f ), which following deprotection of the phenacyl (Pac) group ( 15a – f ) were cyclized using a pentafluorophenyl ester-based macrolactamization to give the corresponding 16-membered macrocycles ( 16a – f ) in good overall yields.…”

Section: Resultsmentioning

confidence: 99%

Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity

et al. 2016

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The problem of antibiotic resistance has prompted the search for new antibiotics with novel mechanisms of action. Analogues of the A54556 cyclic acyldepsipeptides (ADEPs) represent an attractive class of antimicrobial agents that act through dysregulation of caseinolytic protease (ClpP). Previous studies have shown that ADEPs are active against Gram-positive bacteria (e.g., MRSA, VRE, PRSP (penicillin-resistant Streptococcus pneumoniae)); however, there are currently few studies examining Gram-negative bacteria. In this study, the synthesis and biological evaluation of 14 novel ADEPs against a variety of pathogenic Gram-negative and Gram-positive organisms is outlined. Optimization of the macrocyclic core residues and N-acyl side chain culminated in the development of 26, which shows potent activity against the Gram-negative species Neisseria meningitidis and Neisseria gonorrheae and improved activity against the Gram-positive organisms Staphylococcus aureus and Enterococcus faecalis in comparison with known analogues. In addition, the co-crystal structure of an ADEP-ClpP complex derived from N. meningitidis was solved.

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Section: Resultsmentioning

confidence: 99%

Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity

et al. 2016

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“…9 To the best of our knowledge, Schmidt's macrolactamization of 4 (Scheme 1) represents the only known approach for the construction of the 16-membered core (3) and was used in the total synthesis of the structurally related enopeptin B. 10 Although this approach has provided access to the ADEP natural products 7 and related analogues (e.g., 2, Figure 1), 9,11 it suffers inherent disadvantages from a practicality standpoint (e.g., 16 solution-phase synthesis steps, several intermediate purifications, and the use of many protecting groups). Conversely, a semiautomated approach using solid-phase peptide synthesis (SPPS) for assembly of the linear peptide (of general structure 5) via Fmoc chemistry, followed by macrolactonization of the corresponding seco acid, would enable rapid access to analogues for future biological studies.…”

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confidence: 99%

“…For example, the synthetic analog ADEP 4 ( 2 , Figure ) developed by Bayer has shown potent antibacterial activity against multidrug-resistant isolates of S. aureus , S. pneumoniae , and enterococci species in vitro as well as in mice . To the best of our knowledge, Schmidt’s macrolactamization of 4 (Scheme ) represents the only known approach for the construction of the 16-membered core ( 3 ) and was used in the total synthesis of the structurally related enopeptin B . Although this approach has provided access to the ADEP natural products and related analogues (e.g., 2 , Figure ), , it suffers inherent disadvantages from a practicality standpoint (e.g., 16 solution-phase synthesis steps, several intermediate purifications, and the use of many protecting groups).…”

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confidence: 99%

A Lanthanide(III) Triflate Mediated Macrolactonization/Solid-Phase Synthesis Approach for Depsipeptide Synthesis

2015

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The effect of dysprosium(III) triflate on macrolactonization reactions to form depsipeptides using MNBA (Shiina's reagent) is reported. Improved yields were obtained for the formation of 16-membered depsipeptides using lanthanide triflate additives. The use of a macrocyclization strategy permits the use of a semiautomated solid-phase synthesis approach for the rapid synthesis of analogues of the antibacterial A54556 acyldepsipeptides in only two physical operations, requiring only final product purification after cyclization.

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“…A total synthesis was described in 1997. [82] Researchers at Bayer have revised the initial structure of A54556A, [83] and have determined the mechanism of action. [84] The conformation has also been studied by NMR in DMSO solution.…”

Section: Enopeptinsmentioning

confidence: 99%

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics

Obrecht¹,

Robinson²,

Bernardini

et al. 2009

CMC

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O (2009Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics AbstractNovel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents. Abstract:Novel therapeutic strategies are urgently needed for the treatment of serious

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Synthesis of Enopeptin B from Streptomyces sp RK‐1051

Cited by 16 publications

References 24 publications

Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity

Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity

A Lanthanide(III) Triflate Mediated Macrolactonization/Solid-Phase Synthesis Approach for Depsipeptide Synthesis

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics

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