Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents

Anthracycline anticancer drugs doxorubicin and aclarubicin have
been used in the clinic for several decades to treat various cancers.
Although closely related structures, their molecular mode of action
diverges, which is reflected in their biological activity profile.
For a better understanding of the structure–function relationship
of these drugs, we synthesized ten doxorubicin/aclarubicin hybrids
varying in three distinct features: aglycon, glycan, and amine substitution
pattern. We continued to evaluate their capacity to induce DNA breaks,
histone eviction, and relocated topoisomerase IIα in living
cells. Furthermore, we assessed their cytotoxicity in various human
tumor cell lines. Our findings underscore that histone eviction alone,
rather than DNA breaks, contributes strongly to the overall cytotoxicity
of anthracyclines, and structures containing N,N-dimethylamine at the reducing sugar prove that are more
cytotoxic than their nonmethylated counterparts. This structural information
will support further development of novel anthracycline variants with
improved anticancer activity.