Re-Exploring the Anthracycline Chemical Space for Better Anti-Cancer Compounds

J Med Chem. 2023 Aug 24;66(16):11390-11398. doi: 10.1021/acs.jmedchem.3c00853.

Merle A van Gelder ¹, Sabina Y van der Zanden ¹, Merijn B L Vriends ², Roos A Wagensveld ¹, Gijsbert A van der Marel ², Jeroen D C Codée ², Herman S Overkleeft ², Dennis P A Wander ¹, Jacques J C Neefjes ¹

Affiliations

1 Department of Cell and Chemical Biology, ONCODE Institute, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
2 Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.

PMID: 37561481 DOI: 10.1021/acs.jmedchem.3c00853

Abstract

The anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the induction of chromatin damage was introduced as another major determinant of anti-cancer activity. The combination of these two events results in their reported side effects. While our knowledge on the structure-activity relationship of anthracyclines has improved, many structural variations remain poorly explored. Therefore, we here report on the preparation of a diverse set of anthracyclines with variations within the sugar moiety, amine alkylation pattern, saccharide chain and aglycone. We assessed the cytotoxicity in vitro in relevant human Cancer cell lines, and the capacity to induce DNA- and chromatin damage. This coherent set of data allowed us to deduce a few guidelines on anthracycline design, as well as discover novel, highly potent anthracyclines that may be better tolerated by patients.

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