Modification of Anthracyclines to Reduce Cardiotoxicity and Improve Potency Against Cancer Cell Lines

Document Type

Student Presentation

Presentation Date

April 2016

Faculty Sponsor

Don Warner


Cancer is still a leading cause of death in the US, with approximately 1.7 million new cases of disease reported every year and nearly 600,000 deaths. In contrast to the declining trends in incidence and mortality reported for most cancers, soft tissue sarcomas (STS) still have poor survival rates. Complicating this prognosis, one of the few treatments for advanced or metastatic STS is doxorubicin (DOX), a drug with well-known cardiotoxic side effects that limit its lifetime use, even when it is effective in blocking tumor progression. Further, cancer resistance to DOX therapy is problematic and DOX may have to be discontinued because it has lost anticancer activity. To overcome these limiting characteristics of DOX, we have prepared DOX analogs that have been chemically engineered to remove cardiotoxicity and attenuate cancer resistance while retaining the features responsible for chemotherapeutic potency. Specifically, cardiotoxicity has been attributed to the anthraquinone moiety and the C13 carbonyl. The primary amine on DOX’s daunosamine sugar is thought to be responsible for drug resistance. As such, we have prepared analogs where these functional groups have been excised or modified for electrophilic functionality. Although preliminary in vitro and in vivo activity studies have yielded analogs with varying degrees of promise, one analog has displayed anticancer activity that is 60-fold greater than DOX against SW-872 cell cultures, a human liposarcoma cell line. However, the presence or absence of drug-induced cardiotoxicity is unknown. The preparation and characterization of the new semi-synthetic analogs will be presented, as will preliminary cell culture experiments assessing cytotoxicity.

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