# Repositioning HDAC Inhibitors for Glioma Treatment: Synthesis and Biological Evaluation

## TL;DR

This study explores new HDAC inhibitors as potential treatments for gliomas, showing promising anti-cancer effects in laboratory tests.

## Contribution

The paper introduces novel hydroxamate- and benzamide-based HDAC inhibitors with selective enzyme inhibition and favorable drug profiles for glioma therapy.

## Key findings

- Compound 3a and 6a induced cell cycle arrest and apoptosis in glioma cells.
- Compound 6a showed higher potency in glioblastoma stem cells.
- Molecular simulations confirmed selective HDAC inhibition and favorable pharmacokinetics.

## Abstract

Gliomas are a type of brain tumor associated with poor
patient
prognosis, with current treatment, surgical resection when feasible,
followed by radiotherapy and chemotherapy (Temozolomide), yielding
a median survival of approximately 15 months. In light of the urgent
need for more effective therapies, histone deacetylases (HDACs) have
emerged as promising targets, given their differential expression
across tumor types and disease grades. Although HDAC inhibitors are
well established in the treatment of hematological malignancies, their
potential is now being explored in solid tumors, including glioblastoma
(GBM). In this study, hydroxamate-based (3a) and benzamide-based
(6a) HDAC inhibitors were synthesized and evaluated in
glioma cell lines and glioblastoma stem cells (GSC). Treatment with
these inhibitors resulted in cell cycle alterations, increased SubG1
populations, and enhanced apoptosis, particularly with compound 3a. Notably, 6a demonstrated greater potency
in GSCs. The observed cytotoxic effects were linked to selective inhibition
of HDAC6 by 3a and HDAC1/3 by 6a, as confirmed
through enzymatic assays and further supported by molecular docking
and molecular dynamics (MD) simulations. In silico analyses suggest that both compounds possess favorable pharmacokinetic
profiles, underscoring their potential as promising candidates for
glioma therapy and paving the way for future drug development in this
field.