We propose to complete the total synthesis of anthracycline N-isosteres in which the quinone C=O groups are replaced by N-O. These will be the first anthracycline analogs with changes in the C skeleton of the aglycone that alter, but do not delete, quinone type properties. The only previous anthracycline structure change at the quinone was the 5-iminoquinone, which proved to be noncardiotoxic. We have recently worked out the synthetic methodology to give substituted tetra-hydrobenzo[b]phenazines and their bis-N-oxides as the isosteric aglycones. We now propose to functionalize the A ring and couple it with daunosamine, based on anthracycline chemistry as adapted in our recent model experiments. This general approach will be brought to completion and then applied to several additional analogs, with varied patterns of OH substitution adjacent to the bis N-O ring. Varied OH substitution patterns have been shown to alter biological properties of the anthracyclines. Further modifications of this approach may less directly give the exact isosteres of daunorubicin and doxorubicin, if needed. The isosteric products will be tested for antitumor effects, DNA binding, redox properties relevant to O2 radical formation, and cardiotoxicity. Alterations in the pattern of antitumor effects and/or cardiotoxic side effects may be expected. This is a synthesis-based study in anticancer drug development. These structure changes at the mechanistically important quinone are unique in the anthracycline series. This concept can be applied to other antitumor quinones. The synthesis of simpler hydroxyphenazine bis-N-oxides and thianthrene bis-S-oxides, with amino side chains in both cases, is also proposed in order to begin exploring this concept more broadly.
