Annulation of substituted anthracene-9,10-diones yields promising selectively antiproliferative compounds

Anthraquinone derivatives are well-known antiproliferative compounds, and some are currently used in cancer chemotherapy. Some families of annulated anthraquinone analogs have also been examined for antiproliferative activity, but in this regard almost nothing is known of 1-azabenzanthrones (7H-dibenzo[de,h]quinolin-7-ones). A series of 1-azabenzanthrone derivatives, their 2,3-dihydro analogs, and congruently substituted 9,10-anthracenediones were tested against normal human fibroblasts and four human cancer cell lines. Most of the heterocyclic compounds proved to be weakly to moderately antiproliferative with IC50 values extending down to 0.86 μM, and exhibited up to 30-fold selectivity between cancer and normal cells. Both 1-azabenzanthrones and 1-aza-2,3-dihydrobenzanthrones were more potent than their anthraquinone counterparts, and almost without exception, the 2,3-dihydro compounds were more potent than the fully aromatic 1-azabenzanthrones.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of 1-azabenzanthrones and 2,3-dihydro derivatives were synthesized. ► Their antiproliferative activity was assessed using the MTT reduction assay. ► 2,3-Dihydro compounds were generally more potent than 1-azabenzanthrones. ► Several of the derivatives exhibited low micromolar IC50 values down to 0.86 μM. ► The most potent one was 30-fold selective against cancer vs. normal cells.