Anthracyclines: biosynthesis, engineering and clinical applications

Covering: January 1995 to June 2021Anthracyclines are glycosylated microbial natural products that harbour potent antiproliferative activities. Doxorubicin has been widely used as an anticancer agent in the clinic for several decades, but its use is restricted due to severe side-effects such as card...

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Bibliographic Details
Published in:Natural product reports 2022-04, Vol.39 (4), p.814-841
Main Authors: Hulst, Mandy B, Grocholski, Thadee, Neefjes, Jacques J C, van Wezel, Gilles P, Metsä-Ketelä, Mikko
Format: Article
Language:English
Subjects:
Anthracycline
Anthracyclines - metabolism
Anthracyclines - pharmacology
Anticancer properties
Antineoplastic Agents - pharmacology
Antitumor agents
Biosynthesis
Cardiotoxicity
Chemotherapy
Combinatorial analysis
Congeners
DNA damage
DNA topoisomerase (ATP-hydrolysing)
DNA Topoisomerases, Type II - metabolism
Doxorubicin
Doxorubicin - metabolism
Doxorubicin - pharmacology
Histones
Metabolic engineering
Microorganisms
Natural products
Polyketides
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Summary:Covering: January 1995 to June 2021Anthracyclines are glycosylated microbial natural products that harbour potent antiproliferative activities. Doxorubicin has been widely used as an anticancer agent in the clinic for several decades, but its use is restricted due to severe side-effects such as cardiotoxicity. Recent studies into the mode-of-action of anthracyclines have revealed that effective cardiotoxicity-free anthracyclines can be generated by focusing on histone eviction activity, instead of canonical topoisomerase II poisoning leading to double strand breaks in DNA. These developments have coincided with an increased understanding of the biosynthesis of anthracyclines, which has allowed generation of novel compound libraries by metabolic engineering and combinatorial biosynthesis. Coupled to the continued discovery of new congeners from rare Actinobacteria, a better understanding of the biology of and improved production methodologies, the stage is set for the development of novel anthracyclines that can finally surpass doxorubicin at the forefront of cancer chemotherapy.
ISSN:0265-0568
1460-4752
DOI:10.1039/d1np00059d