Anthracyclines are used in the medical field for their antitumor activities. One of the most common drugs of this class, doxorubicin (DOX), has been used to treat cancers in the breasts, ovaries, and lungs. The mode of action for DOX is intercalation between the base pairs of DNA, which disrupts translation and replication. The planar structure of DOX allows the rings to slide in between the base pairs, while the sugar moiety interacts with the minor groove. The sugar connects to the minor groove via hydrogen bonding between the amine of the sugar and the sugar-phosphate backbone of DNA. To determine how the absence of those hydrogen bonding interactions affect the binding mode, a DOX analog (7,10-dihydro-6,11-dihydroxy-naphthacenedione) was synthesized. The analog required a four-step synthesis, starting from hydroquinone and phthalic anhydride; the product was recovered in fairly low purity. The first three rings were built using a variety of Friedal–Crafts and Claisen rearrangement reactions, with a ring closing metathesis to complete the fourth ring. The scheme and final structure can be seen in Scheme 1. Further attempts were also made to introduce an amine group onto this tetracyclic structure, to mimic the DOX amino-sugar, making interaction with the minor grove of the DNA backbone possible, but those efforts have not yet proven successful. This reaction is shown in Scheme 2. &lt;!--![endif]----&gt;

Synthesis of doxorubicin analogs for DNA binding studies

255th National Meeting (2018)

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