Synthesis and in vitro antitumor activity of asperphenamate derivatives as autophagy inducer

Three series of natural product asperphenamate derivatives with improved aqueous solubility were designed and synthesized. The in vitro anticancer activities of all derivatives were investigated. IM23b displayed most potent growth inhibitory activity against MCF-7 cells. The mechanism of cell death induced by IM23b in MCF-7 cells was investigated. The results showed that IM23b caused cell death by the induction of autophagy instead of apoptosis or cell cycle arrest. In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest.