Synthesis and anti-tumor activity evaluation of novel chalcone derivatives as potential HDAC6 inhibitors

Histone deacetylase inhibitors (HDACis) are a class of epigenetic drugs that, as the name suggests, inhibit histone deacetylases (HDACs), which are anticancer therapeutic targets. Several studies have investigated hydroxamic acid HDACi. However, most anti-cancer HDACis are pan-inhibitors with multiple adverse reactions. Compared with traditional anti-tumor drugs, natural products have lower toxicity and are less likely to cause drug resistance in tumor cells. Our previous study identified that chalcone natural products have strong anti-tumor activity in vitro. Therefore, in this study, 27 chalcone derivatives with α, β-unsaturated hydroxamic acid groups were synthesized and evaluated in vitro and in vivo. The results showed that compound 4u had a strong inhibitory effect on SW620 cell proliferation. Furthermore, 4u selectively inhibits HDAC6 activity, as validated by the strong binding affinity observed between 4u and HDAC6. Furthermore, in vitro results were validated by in vivo assays, showing that 4u could inhibit tumor growth and HDAC6 activity in an animal model. These findings confirmed that compound 4u can serve as a lead compound for selective HDAC6 inhibitors and warrant further research as an anti-tumor agent.