Discovery of 2,5-diphenyl-1,3,4-thiadiazole derivatives as HDAC inhibitors with DNA binding affinity

Abstract

Incorporating a DNA-binding fragment in HDAC inhibitors has been proved to be an effective strategy for the treatment of hematologic malignancies by our group. However, similar to other approved HDAC inhibitors, their effects on solid tumor were poor. For this issue, a series of 2,5-diphenyl-1,3,4-thiadiazole hydroxamate derivatives were designed and synthesized as the HDAC inhibitors with DNA binding affinity. Among the target compounds, 4j not only bound with DNA effectively but also exhibited the most potent inhibitory activity against HDAC1 with the IC₅₀ of 15 nM. Compared to SAHA, compound 4j displayed stronger antiproliferative activity in tested tumor cell lines. Western blot analysis showed that 4j could enhance the acetylation of histone H3 and α-tubulin, as well as promote the activation of caspase 3 in HCT116 and MC38 cell lines. Furthermore, these responses resulted in significant suppression of tumor growth in the MC38 tumor model. This work validated that compound 4j was a promising lead compound for further structural optimization.