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Synthetic remodeling of the chartreusin pathway to tune antiproliferative and antibacterial activities.

Natural products of the benzonaphthopyranone class, such as chartreusin, elsamicin A, gilvocarcin, and polycarcin, represent potent leads for urgently needed anticancer therapeutics and antibiotics. Since synthetic protocols for altering their architectures are limited, we harnessed enzymatic promis... Full description

Journal Title: Journal of the American Chemical Society November 20, 2013, Vol.135(46), pp.17408-17416
Main Author: Ueberschaar, Nico
Other Authors: Xu, Zhongli , Scherlach, Kirstin , Metsä-Ketelä, Mikko , Bretschneider, Tom , Dahse, Hans-Martin , Görls, Helmar , Hertweck, Christian
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1520-5126 ; DOI: 1520-5126 ; DOI: 10.1021/ja4080024
Link: http://search.proquest.com/docview/1461337075/?pq-origsite=primo
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recordid: proquest1461337075
title: Synthetic remodeling of the chartreusin pathway to tune antiproliferative and antibacterial activities.
format: Article
creator:
  • Ueberschaar, Nico
  • Xu, Zhongli
  • Scherlach, Kirstin
  • Metsä-Ketelä, Mikko
  • Bretschneider, Tom
  • Dahse, Hans-Martin
  • Görls, Helmar
  • Hertweck, Christian
subjects:
  • Anti-Bacterial Agents–Biosynthesis
  • Antineoplastic Agents–Chemistry
  • Benzopyrans–Pharmacology
  • Cell Line, Tumor–Chemistry
  • Cell Proliferation–Metabolism
  • Dose-Response Relationship, Drug–Pharmacology
  • Drug Screening Assays, Antitumor–Chemistry
  • Enterococcus–Pharmacology
  • Glycosides–Drug Effects
  • Ht29 Cells–Drug Effects
  • Hela Cells–Biosynthesis
  • Humans–Chemistry
  • K562 Cells–Pharmacology
  • Methicillin-Resistant Staphylococcus Aureus–Drug Effects
  • Microbial Sensitivity Tests–Drug Effects
  • Models, Molecular–Drug Effects
  • Molecular Structure–Drug Effects
  • Mycobacterium–Drug Effects
  • Structure-Activity Relationship–Drug Effects
  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Benzopyrans
  • Glycosides
  • Chartreusin
ispartof: Journal of the American Chemical Society, November 20, 2013, Vol.135(46), pp.17408-17416
description: Natural products of the benzonaphthopyranone class, such as chartreusin, elsamicin A, gilvocarcin, and polycarcin, represent potent leads for urgently needed anticancer therapeutics and antibiotics. Since synthetic protocols for altering their architectures are limited, we harnessed enzymatic promiscuity to generate a focused library of chartreusin derivatives. Pathway engineering of the chartreusin polyketide synthase, mutational synthesis, and molecular modeling were employed to successfully tailor the structure of chartreusin. For the synthesis of the aglycones, improved synthetic avenues to substituted coumarin building blocks were established. Using an engineered mutant, in total 11 new chartreusin analogs (desmethyl, methyl, ethyl, vinyl, ethynyl, bromo, hydroxy, methoxy, and corresponding (1→2) abeo-chartreusins) were generated and fully characterized. Their biological evaluation revealed an unexpected impact of the ring substituents on antiproliferative and antibacterial activities. Irradiation of vinyl- and ethynyl-substituted derivatives with blue light resulted in an improved antiproliferative potency against a colorectal cancer cell line. In contrast, the replacement of a methyl group by hydrogen caused a drastically decreased cytotoxicity but markedly enhanced antimycobacterial activity. Furthermore, mutasynthesis of bromochartreusin led to the first crystal structure of a chartreusin derivative that is not modified in the glycoside residue. Beyond showcasing the possibility of converting diverse, fully synthetic polyphenolic aglycones into the corresponding glycosides in a whole-cell approach, this work identified new chartreusins with fine-tuned properties as promising candidates for further development as therapeutics.
language: eng
source:
identifier: E-ISSN: 1520-5126 ; DOI: 1520-5126 ; DOI: 10.1021/ja4080024
fulltext: fulltext
issn:
  • 15205126
  • 1520-5126
url: Link


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titleSynthetic remodeling of the chartreusin pathway to tune antiproliferative and antibacterial activities.
creatorUeberschaar, Nico ; Xu, Zhongli ; Scherlach, Kirstin ; Metsä-Ketelä, Mikko ; Bretschneider, Tom ; Dahse, Hans-Martin ; Görls, Helmar ; Hertweck, Christian
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subjectAnti-Bacterial Agents–Biosynthesis ; Antineoplastic Agents–Chemistry ; Benzopyrans–Pharmacology ; Cell Line, Tumor–Chemistry ; Cell Proliferation–Metabolism ; Dose-Response Relationship, Drug–Pharmacology ; Drug Screening Assays, Antitumor–Chemistry ; Enterococcus–Pharmacology ; Glycosides–Drug Effects ; Ht29 Cells–Drug Effects ; Hela Cells–Biosynthesis ; Humans–Chemistry ; K562 Cells–Pharmacology ; Methicillin-Resistant Staphylococcus Aureus–Drug Effects ; Microbial Sensitivity Tests–Drug Effects ; Models, Molecular–Drug Effects ; Molecular Structure–Drug Effects ; Mycobacterium–Drug Effects ; Structure-Activity Relationship–Drug Effects ; Anti-Bacterial Agents ; Antineoplastic Agents ; Benzopyrans ; Glycosides ; Chartreusin
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descriptionNatural products of the benzonaphthopyranone class, such as chartreusin, elsamicin A, gilvocarcin, and polycarcin, represent potent leads for urgently needed anticancer therapeutics and antibiotics. Since synthetic protocols for altering their architectures are limited, we harnessed enzymatic promiscuity to generate a focused library of chartreusin derivatives. Pathway engineering of the chartreusin polyketide synthase, mutational synthesis, and molecular modeling were employed to successfully tailor the structure of chartreusin. For the synthesis of the aglycones, improved synthetic avenues to substituted coumarin building blocks were established. Using an engineered mutant, in total 11 new chartreusin analogs (desmethyl, methyl, ethyl, vinyl, ethynyl, bromo, hydroxy, methoxy, and corresponding (1→2) abeo-chartreusins) were generated and fully characterized. Their biological evaluation revealed an unexpected impact of the ring substituents on antiproliferative and antibacterial activities. Irradiation of vinyl- and ethynyl-substituted derivatives with blue light resulted in an improved antiproliferative potency against a colorectal cancer cell line. In contrast, the replacement of a methyl group by hydrogen caused a drastically decreased cytotoxicity but markedly enhanced antimycobacterial activity. Furthermore, mutasynthesis of bromochartreusin led to the first crystal structure of a chartreusin derivative that is not modified in the glycoside residue. Beyond showcasing the possibility of converting diverse, fully synthetic polyphenolic aglycones into the corresponding glycosides in a whole-cell approach, this work identified new chartreusins with fine-tuned properties as promising candidates for further development as therapeutics.
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titleSynthetic remodeling of the chartreusin pathway to tune antiproliferative and antibacterial activities.
authorUeberschaar, Nico ; Xu, Zhongli ; Scherlach, Kirstin ; Metsä-Ketelä, Mikko ; Bretschneider, Tom ; Dahse, Hans-Martin ; Görls, Helmar ; Hertweck, Christian
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