Conjugating Daunorubicin and Doxorubicin to GTP by Formaldehyde to Overcome Drug Resistance

Daunorubicin and doxorubicin are among the most potent anti‐cancer drugs and bind to DNA through intercalation. In this paper, we demonstrate that formaldehyde can efficiently and specifically conjugate daunorubicin and doxorubicin to GTP, resulting in the formation of daunorubicin‐GTP‐1 and doxorubicin‐GTP‐1 conjugates. The linkage occurs between the 2‐NH 2 of guanine and the 3’‐NH 2 of daunosamine. We characterized these daunorubicin/doxorubicin‐GTP conjugates using various methods, including UV‐Vis, fluorescence, CD, FT‐IR, and mass spectrometry. Our results also indicate that these daunorubicin/doxorubicin‐GTP conjugates bind to DNA via intercalation. Furthermore, we observed rapid accumulation of these conjugates in human cancer cells and observed cytotoxic effects in both doxorubicin‐sensitive SK‐OV‐3 and doxorubicin‐resistant NCI/ADR‐RES cells, suggesting that these daunorubicin and doxorubicin derivatives can overcome doxorubicin resistance.