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

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.