Repositioning HDAC Inhibitors for Glioma Treatment: Synthesis and Biological Evaluation

Area of Science:

• Oncology
• Neuro-oncology
• Medicinal Chemistry

Background:

• Gliomas, particularly glioblastoma (GBM), have poor prognoses with current treatments.
• Histone deacetylases (HDACs) are emerging targets for cancer therapy, with inhibitors established for hematological malignancies.
• Exploring HDAC inhibitors for solid tumors like gliomas is a critical area of research.

Purpose of the Study:

• To synthesize and evaluate novel hydroxamate-based (3a) and benzamide-based (6a) HDAC inhibitors.
• To assess the efficacy of these compounds in glioma cell lines and glioblastoma stem cells (GSCs).
• To elucidate the mechanism of action and pharmacokinetic profiles of the synthesized HDAC inhibitors.

Main Methods:

• Synthesis of hydroxamate-based (3a) and benzamide-based (6a) HDAC inhibitors.
• In vitro evaluation in glioma cell lines and GSCs, assessing cell cycle, apoptosis, and cytotoxicity.
• Enzymatic assays, molecular docking, and molecular dynamics simulations to confirm target inhibition and analyze pharmacokinetics.

Main Results:

• Both compounds induced cell cycle arrest, increased SubG1 populations, and enhanced apoptosis in glioma cells.
• Compound 3a showed significant effects, linked to selective HDAC6 inhibition.
• Compound 6a demonstrated greater potency in GSCs, associated with HDAC1/3 inhibition.
• In silico analyses indicated favorable pharmacokinetic profiles for both compounds.

Conclusions:

• Novel HDAC inhibitors 3a and 6a exhibit potent anti-glioma activity.
• Selective inhibition of specific HDACs (HDAC6 by 3a, HDAC1/3 by 6a) underlies their cytotoxic effects.
• These compounds represent promising candidates for future glioma therapeutic development.