One-pot synthesis of oxoaporphines as potent antitumor agents and investigation of their mechanisms of actions.

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC 50 value of 0.5 μM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by −NO 2 significantly enhanced the anticancer activity. Mechanism studies indicated that 4 and 4B induced cell cycle arrest at G2/M phase; in contrast, 4V induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds 4 , 4B and 4V , suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24. [Display omitted] • One-pot reaction for synthesis of oxoaporphine alkaloids was developed. • A series of oxoaporphine alkaloids were synthesized. • 4B induced DNA damage, and caused significant G2/M cell cycle arrest. • 4B induced caspase-3/9-dependent apoptosis through mitochondrial dysfunction. • 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24. [ABSTRACT FROM AUTHOR]