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Exploiting enzymatic promiscuity to engineer a focused library of highly selective antifungal and antiproliferative aureothin analogues.

Aureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring, and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its... Full description

Journal Title: Journal of the American Chemical Society August 4, 2010, Vol.132(30), pp.10407-10413
Main Author: Werneburg, Martina
Other Authors: Busch, Benjamin , He, Jing , Richter, Martin E A , Xiang, Longkuan , Moore, Bradley S , Roth, Martin , Dahse, Hans-Martin , Hertweck, Christian
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1520-5126 ; DOI: 10.1021/ja102751h
Link: http://search.proquest.com/docview/748931153/?pq-origsite=primo
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title: Exploiting enzymatic promiscuity to engineer a focused library of highly selective antifungal and antiproliferative aureothin analogues.
format: Article
creator:
  • Werneburg, Martina
  • Busch, Benjamin
  • He, Jing
  • Richter, Martin E A
  • Xiang, Longkuan
  • Moore, Bradley S
  • Roth, Martin
  • Dahse, Hans-Martin
  • Hertweck, Christian
subjects:
  • Animals–Chemistry
  • Antibiotics, Antineoplastic–Metabolism
  • Antifungal Agents–Pharmacology
  • Cell Line, Tumor–Chemistry
  • Cell Proliferation–Metabolism
  • Chromones–Pharmacology
  • Fungi–Drug Effects
  • Humans–Chemistry
  • Mycoses–Metabolism
  • Neoplasms–Pharmacology
  • Streptomyces–Drug Effects
  • Streptomyces–Drug Therapy
  • Streptomyces–Drug Therapy
  • Streptomyces–Chemistry
  • Streptomyces–Enzymology
  • Streptomyces–Metabolism
  • Antibiotics, Antineoplastic
  • Antifungal Agents
  • Chromones
  • Aureothin
ispartof: Journal of the American Chemical Society, August 4, 2010, Vol.132(30), pp.10407-10413
description: Aureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring, and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its bioactivity profile. In an integrated approach using mutasynthesis, biotransformation, and combinatorial biosynthesis, a defined library of aureothin analogues was generated. The promiscuity of the polyketide synthase assembly line toward different starter units and the plasticity of the pyrone and tetrahydrofuran ring formation were exploited. A selection of 15 new aureothin analogues with modifications at the aryl residue, the pyrone ring, and the oxygenated backbone was produced on a preparative scale and fully characterized. Remarkably, various new aureothin derivatives are less cytotoxic than aureothin but have improved antiproliferative activities. Furthermore, we found that the THF ring is crucial for the remarkably selective activity of aureothin analogues against certain pathogenic fungi.
language: eng
source:
identifier: E-ISSN: 1520-5126 ; DOI: 10.1021/ja102751h
fulltext: fulltext
issn:
  • 15205126
  • 1520-5126
url: Link


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titleExploiting enzymatic promiscuity to engineer a focused library of highly selective antifungal and antiproliferative aureothin analogues.
creatorWerneburg, Martina ; Busch, Benjamin ; He, Jing ; Richter, Martin E A ; Xiang, Longkuan ; Moore, Bradley S ; Roth, Martin ; Dahse, Hans-Martin ; Hertweck, Christian
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identifierE-ISSN: 1520-5126 ; DOI: 10.1021/ja102751h
subjectAnimals–Chemistry ; Antibiotics, Antineoplastic–Metabolism ; Antifungal Agents–Pharmacology ; Cell Line, Tumor–Chemistry ; Cell Proliferation–Metabolism ; Chromones–Pharmacology ; Fungi–Drug Effects ; Humans–Chemistry ; Mycoses–Metabolism ; Neoplasms–Pharmacology ; Streptomyces–Drug Effects ; Streptomyces–Drug Therapy ; Streptomyces–Drug Therapy ; Streptomyces–Chemistry ; Streptomyces–Enzymology ; Streptomyces–Metabolism ; Antibiotics, Antineoplastic ; Antifungal Agents ; Chromones ; Aureothin
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descriptionAureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring, and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its bioactivity profile. In an integrated approach using mutasynthesis, biotransformation, and combinatorial biosynthesis, a defined library of aureothin analogues was generated. The promiscuity of the polyketide synthase assembly line toward different starter units and the plasticity of the pyrone and tetrahydrofuran ring formation were exploited. A selection of 15 new aureothin analogues with modifications at the aryl residue, the pyrone ring, and the oxygenated backbone was produced on a preparative scale and fully characterized. Remarkably, various new aureothin derivatives are less cytotoxic than aureothin but have improved antiproliferative activities. Furthermore, we found that the THF ring is crucial for the remarkably selective activity of aureothin analogues against certain pathogenic fungi.
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