Cancer is the second leading cause of death in the United State, surpassed only by heart disease. In 2016, there will be an estimated 1.6 million new cases along with nearly 600,000 deaths. The anthracycline Doxorubicin (DOX) is an important and effective anti-cancer agent. However, its use is severely limited due to the risk of irreversible dose dependent cardiomyopathy and eventual congestive heart failure, limiting the maximum lifetime cumulative dose to only 550 mg/m<sup>2</sup>. To eliminate this cardiotoxicity, a new analog, GPX150, was synthesized through several steps: removal of DOX’s C-13 carbonyl followed by conversion of the quinone moiety to a less reactive iminoquinone species. The alterations, while alleviating the cardiotoxic side effects, decrease the potency of the drug fourfold, translating into a significantly higher cost for treatment. As well, several cancer cell lines, initially quite sensitive to DOX, have shown insensitivity to GPX150. Modification of the 3’-amine of DOX’s sugar moiety with electrophilic substituents such as a pyrrolino, propyrrolino, morpholino, and cyanomorpholino have resulted in 100-1000 times increase in observed potency. This drastic increase in potency has been attributed to the electrophilic moieties being able to form covalent aminal adducts between the DOX compound and amino containing groups such as guanine bases of the DNA. Presumably, the covalent DNA linkage is responsible for the observed intensification as an anti-cancer agent. A variety of GPX150 analogs with differing electrophilic moieties have been synthesized with yields up to 90% and purity greater than 95%, as determined by mass spectrometry and NMR spectroscopy. Preliminary results indicate that, compared to GPX150, the new analogs have increased efficacy against a variety of cancer cell lines. In one instance, for example, the new compound is 10-30 times more potent than GPX150 and has activity typically equivalent to DOX. These and related results will be presented.

Potent but potentially non-cardiotoxic anthracycline anti-cancer analogs

253rd National Meeting (2017)

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