In the search for new potentially anticancer drugs, series of angucyclinone aza-analogues containing pyridine and pyridopyridazine rings have been designed and synthesized by a highly efficient sequence involving a one-pot step for the synthesis of tricyclic quinone intermediate and highly regiocontrolled cycloaddition reactions with polarized 1,3-dienes. The new N-heterocyclic angular quinones were evaluated in vitro on normal human fibroblasts and on a panel of four distinct human cancer cell lines. All tested compounds showed high to moderate antitumor activity. Among the compounds, those with one and two pyridine moieties fused to the quinone system have shown the best effect. Structure-activity relationships established the main structural requirement for the activity of the new potential anticancer drugs.