Phenylimino-10H-anthracen-9-ones as novel antimicrotubule agents-synthesis, antiproliferative activity and inhibition of tubulin polymerization

A novel series of phenylimino-10H-anthracen-9-ones and 9-(phenylhydrazone)-9,10-anthracenediones were synthesized and evaluated for interaction with tubulin and for cytotoxicity against a panel of human tumor cell lines. The 10-(3-hydroxy-4-methoxy-phenylimino)-10H-anthracen-9-one 15h and its dichloro analog 16b were identified as potent inhibitors of tumor cell growth (16b, IC(50) K562 0.11 μM), including multidrug resistant phenotypes. Compound 15h had excellent activity as an inhibitor of tubulin polymerization. Concentration-dependent cell cycle analyzes by flow cytometry confirmed that KB/HeLa cells treated by 15h and 16b were arrested in the G2/M phases of the cell cycle. In competition experiments, 15h strongly displaced radiolabeled colchicine from its binding site on tubulin, showing IC(50) values similar to that of colchicine. The results obtained demonstrate that the antiproliferative activity is related to the inhibition of tubulin polymerization.