Novel cinnamaldehyde-based aspirin derivatives for the treatment of colorectal cancer.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. Current treatments of CRC involve anti-cancer agents with relatively good efficacy but unselectively target both cancer and non-cancer cells. Thus, there is a need to discover and develop novel CRC therapeutics that have potent anti-cancer effects, but show reduced off-target cell effects. Here, a novel series of cinnamaldehyde-based aspirin derivatives were designed and synthesized. Biological evaluation indicated that the most active compound 1f exhibited more than 10-fold increase in the anti-proliferation efficacy in HCT-8 cells compared to the parent compounds. Its effects were similarly reproduced in another CRC cell line, DLD-1, but with 7- to 11-fold less inhibitory activity in non-tumorigenic colon cells. Flow cytometry analysis showed that 1f induced cell cycle arrest and apoptosis, which was further validated with immunoblot analysis of the relative protein levels of cleaved caspase 3 and PARP as well as the ROS production in CRC cells. More so, 1f significantly inhibited the growth of implanted CRC in vivo in mouse xenograft model. Taken together, our results show that cinnamaldehyde-based aspirin derivatives such as 1f show promise as novel anti-CRC agent for further pharmaceutical development.