Synthesis and cytotoxic activity of acronycine derivatives modified at the pyran ring

Nitration of acronycine (1) and 6-demethoxyacronycine (3) afforded 2-nitroacronycine (2) and 2-nitro-6-demethoxyacronycine (4), respectively. Reduction of 2-nitroacronycine yielded, depending on the conditions, 2-nitro-1,2-dihydroacronycine (5), 2-oxo-1,2-dihydroacronycine oxime (7) or 2-amino-1,2-dihydroacronycine (6). This latter was readily converted into 2-dimethylamino-1,2-dihydroacronycine (8), 2-acetylamino-1,2-dihydro-acronycine (9) and 2-benzoylamino-1,2-dihydroacronycine (10). The cytotoxicity of these compounds was evaluated against L1210 leukemia cells. Compounds 2 and 7 were 300- and 10-fold more potent than acronycine in inhibiting L1210 cell proliferation, respectively. Compound 2 was devoid of antitumor activity against P388 leukemia and C38 colon adenocarcinoma.