A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma

Glioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA, from the structural modification of natural product curcumin. DMC-HAs were tested in an HDAC inhibition assay and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cytotoxicity. It showed potent inhibition of HDAC1–2 and HDAC6 with IC(50) values in the submicromolar concentration range. DMC-HA significantly inhibited the proliferation of human glioblastoma U87 cells and mediated apoptosis of U87 cells in a dose- and time-dependent manner. In addition, DMC-HA elevated the acetylation level of histone H3 in U87 cells. Pharmacokinetic studies showed that DMC-HA possessed acceptable pharmacokinetic profiles, accompanied with certain brain permeability. Lastly, we showed that DMC-HA suppressed the growth of tumor in U87 tumor xenograft model in vivo with no obvious toxicity. These results demonstrate that DMC-HA has the potential to be developed as a chemotherapeutic drug for GBM patients.