Chemical cross‐linking of doxorubicin to synthetic oligonucleotides by formaldehyde

Anthacycline antibiotics, such as doxorubicin and daunorubicin, are among the most effective anti‐cancer drugs that treat various cancers. Previous research has shown that doxorubicin and daunorubicin were efficiently cross‐linked to double‐stranded (ds) DNA in the presence of formaldehyde in a regioselective and base specific manner. In an effort to further explore the cross‐linking of anthracycline antibiotics to DNA, doxorubicin is crosslinked to a variety of synthetic oligonucleotides including sequence specific ds and single stranded (ss) DNA oligomers. Our results demonstrate that doxorubicin is able to efficiently crosslink to the N2 amino group of guanine for the ds DNA oligomers. Intriguingly, we also discovered that doxorubicin is able to crosslink to ssDNA and ssRNA specifically to guanine residues by formaldehyde. These results suggest that ssDNA and ssRNA may serve as a new delivery system for the treatment of cancer patients by doxorubicin and daunorubicin. Support or Funding Information 1R15GM109254‐01A1; R25GM061347