Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Bearing a Pyrazole Scaffold and a Cinnamoyl Linker

Genetic abnormalities have been conventionally considered as hallmarks of cancer.
However, recent studies have demonstrated that epigenetic mechanisms are also implicated
in the insurgence and development of cancer. Patterns of the epigenetic component include
DNA methylation and histone modifications. Acetylation of histones is controlled by histone
acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic
systems is known to be a key factor in tumor progression. Because HDACs have been found to
function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as
cancer chemotherapeutics. Herein, we report the synthesis, docking studies and biological activity of
a series of hydroxamic acid-based HDACIs bearing an N1-aryl or N1-H pyrazole nucleus as surface
recognition motif and a cinnamoyl group as a linker to the hydroxamic acid zinc-binding group (ZBG).
Some of the tested compounds exhibited inhibitory properties towards HDACs and antiproliferative
activity against neuroblastoma SH-SY5Y tumor cell line both at micromolar concentrations.