Anthracyclines: biosynthesis, engineering and clinical applications

: Hulst Mandy B., Grocholski Thadee, Neefjes Jacques J.C., van Wezel Gilles P., Metsä-Ketelä Mikko

Publisher: Royal Society of Chemistry

: 2022

: Natural Product Reports

: NATURAL PRODUCT REPORTS

: NAT PROD REP

: 39

: 4

: 814

: 841

: 28

: 0265-0568

: 1460-4752

DOI: https://doi.org/10.1039/d1np00059d

Covering: January 1995 to June 2021 Anthracyclines 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 Streptomyces 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.