Solid‐Phase Synthesis of Aza‐Kahalalide F Analogues: (2<i>R</i>,3<i>R</i>)‐2‐Amino‐3‐azidobutanoic Acid as Precursor of the Aza‐Threonine

Izzo, Irene; Acosta, Gerardo; Tulla‐Puche, Judit; Cupido, Tommaso; Martin‐Lopez, M. J.; Cuevas, Carmen; Alberício, Fernando

doi:10.1002/ejoc.200901345

Cited by 13 publications

(6 citation statements)

References 31 publications

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“…[7] In addition, there is substantial evidence in the literature showing that substitution of the ester bond in depsipeptides with an amide bond may afford derivatives with comparable activities and markedly increased serum stabilities. [63–65] With this in mind, we synthesized eighteen fusaricidin A/LI-F04a analogs and investigated the effects of structural modification on their overall hydrophobicity/amphiphilicity, conformation, stability and biological activity. All analogs were synthesized on a solid support using Fmoc methodology.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

et al. 2012

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Bacterial infections are becoming increasingly difficult to treat due to the development and spread of antibiotic resistance. Therefore, identifying novel antibacterial targets and new antibacterial agents capable of treating infections from drug-resistant bacteria is of vital importance. Structurally simple, yet potent fusaricidin or LI-F class of natural products represents a particularly attractive source of candidates for the development of new antibacterial agents. We have synthesized eighteen fusaricidin/LI-F analogs and investigated the effect of their structure modification on conformation, serum stability, antibacterial activity and human cell toxicity. Our findings show that substitution of an ester bond in depsipeptides with an amide bond may afford equally potent analogs with improved stability and greatly decreased cytotoxicity. Lower overall hydrophobicity/amphiphilicity of amide analogs in comparison to their parent depsipeptides, as indicated by the HPLC retention times, may explain dissociation of antibacterial activity and human cell cytotoxicity. These results indicate that amide analogs may have significant advantages over fusaricidin/LI-F natural products and their depsipeptide analogs as lead structures for the development of new antibacterial agents.

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Section: Discussionmentioning

confidence: 99%

“…The synthesis started by attaching Fmoc-D-Ala-OH (4 eq.) to the resin using an equimolar amount of DIEA in CH 2 Cl 2 followed by resin endcapping with MeOH, [65] and the chain elongation using standard Fmoc-chemistry. Quantitative Fmoc substitution of the resin (0.5 mmol/g) was determined by Fmoc cleavage and absorption measurement at 304 nm.…”

Section: Methodsmentioning

confidence: 99%

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

et al. 2012

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“…In an interesting approach, six analogues of KF have been prepared using aza-threonine thus generating amides as isosteres for the original depsi bond. 414 Biological data on these analogues are not yet available.…”

Section: Green Algaementioning

confidence: 99%

Marine natural products

et al. 2012

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Covering: 2010. Previous review: Nat. Prod. Rep., 2011, 28, 196. This review covers the literature published in 2010 for marine natural products, with 895 citations (590 for the period January to December 2010) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1003 for 2010), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.

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“…Reduction of the azide group of the resin-bound Boc-Ala- d -azido-Thr-Gln(Trt) to an amino group proved challenging. Treatment with stannous chloride (SnCl 2 , PhSH, DIPEA) resulted in approximately 60% conversion after four treatments with the reducing cocktail; Staudinger reduction (Ph 3 P and H 2 O/THF) stalled at the iminophosphorane intermediate, and no hydrolysis to the amine was observed, even at high temperatures (50 °C) and in various mixtures of solvents. Saneyoshi et al reported a derivative of triphenylphosphine, triphenylphosphine-2-carboxamide (Ph 2 P- o -C 6 H 4 CONH 2 ), which contains an ortho-carboxamide group to facilitate the hydrolysis of the imino-phosphorane intermediate by providing anchimeric assistance .…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Study of Lactam and Ring-Expanded Analogues of Teixobactin

Yang

Pishenko

et al. 2019

J. Org. Chem.

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This paper describes the chemical synthesis, X-ray crystallographic structure, and antibiotic activity assay of lactam analogues of teixobactin and explores ring-expanded analogues of teixobactin with β 3 -homo amino acids. Lactam analogues of teixobactin containing all four stereoisomers of azathreonine at position 8 were synthesized on a solid support from commercially available stereoisomeric threonine derivatives. The threonine stereoisomers are converted to the diastereomeric aza-threonines by mesylation, azide displacement, and reduction during the synthesis. D-aza-Thr 8 ,Arg 10 -teixobactin exhibits 2-8-fold greater antibiotic activity than the corresponding macrolactone Arg 10 -teixobactin. Aza-teixobactin analogues containing other stereoisomers of aza-threonine are inactive. A dramatic 16-128-fold increase in the activity of teixobactin and teixobactin analogues is observed with the inclusion of 0.002% of the mild detergent polysorbate 80 in the MIC assay. The X-ray crystallographic structure of N-Me-D-Gln 4 ,D-aza-Thr 8 ,Arg 10 -teixobactin reveals an amphipathic hydrogen-bonded antiparallel β-sheet dimer that binds chloride anions. In the binding site, the macrolactam amide NH groups of residues 8, 10, and 11, as well as the extra amide NH group of the lactam ring, hydrogen bond to the chloride anion. The teixobactin pharmacophore tolerates ring expansion of the 13-membered ring to 14-,15-, and 16-membered rings containing β 3 -homo amino acids with retention of partial or full antibiotic activity.

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Solid‐Phase Synthesis of Aza‐Kahalalide F Analogues: (2R,3R)‐2‐Amino‐3‐azidobutanoic Acid as Precursor of the Aza‐Threonine

Cited by 13 publications

References 31 publications

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

Effects of Cyclic Lipodepsipeptide Structural Modulation on Stability, Antibacterial Activity, and Human Cell Toxicity

Marine natural products

Design, Synthesis, and Study of Lactam and Ring-Expanded Analogues of Teixobactin

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