Novel Doxorubicin Derivatives for Reduced Toxicity: An In Silico Study

Doxorubicin is a chemotherapy drug, classified as an anthracycline antibiotic, and has been used as a form of treatment since the 1960s. It is used to treat various cancers, including blood cancers, such as leukemia and lymphoma, as well as solid tumors, such as breast, bladder, lung, and ovarian cancer. Doxorubicin can inhibit the growth and kill cancer cells at any stage, making it one of the most effective chemotherapy drugs. The majority of chemotherapy drugs have severe side effects, as their cytotoxic nature forces them to target healthy cells in addition to cancerous cells. Doxorubicin, in particular, is one of the most toxic chemotherapy drugs and can lead to life-threatening cardiac conditions. Doxorubicin’s toxicity limits its potential and effectiveness, as doses are administered cautiously, with the maximum lifetime cumulative dose being 550 milligrams per square meter. This study aims to reduce the toxicity of doxorubicin by developing five alternative derivatives that lower toxicity levels while maintaining the function of the original compound. All five derivatives showed improvement in toxicity, with the most significant changes in derivative 4. Derivative 4 completely removed the risk of neurotoxicity and cytotoxicity and reduced the toxicity of four groups by at least 26%, some up to 33%. Since the backbone structure remained unchanged, the mechanism of action is likely the same. While these derivatives still need to be further explored and tested through clinical trials, they are a promising alternative for safer and less harmful versions of doxorubicin.