Histone deacetylases (HDACs) have been great research targets for cancer treatment since their irregular expression due to abnormal epigenetic change was known as a significant cause of tumor onset and progression. Recently, HDAC inhibitors are reported to stabilize a tumor suppressor called runt-related transcription factor 3 (RUNX3) and recover its anticancer activity. In the previous study, we introduced a new approach to cancer treatment using HDAC inhibitors that restores RUNX3 activity and presenteda series of novel compounds to recover RUNX3 activity. In this study, we reported a new series of HDAC inhibitors withan alkenyl linker between the core and the cap group to improve chemical and biological properties. Through structure-activity relationship study, we found that the introduction of an alkenyl group enhanced structural rigidity, aiding compound fit better into the HDAC active site, and increased metabolic stability. We conducted in vitro biological assay to select compounds with high level of activity and metabolic stability. Then, we analyzed in vivo anti-cancer effect of the selected compounds in a xenograft regression model using gastric cancer cell lines. Compound 7k showed the highest inhibition level of tumor growth, so it was selected for further pharmacokinetic evaluation. Showing a high oral bioavailability, compound 7k is a prospect candidate for anticancer chemotherapeutic agent with high efficacy and metabolic stability.
IoT, Agriculture, plant health, Crop monitoring.