Quinolone-based HDAC inhibitors

Area of Science:

• Medicinal Chemistry
• Oncology
• Drug Discovery

Background:

• Histone deacetylase (HDAC) inhibitors are a promising class of anticancer drugs, with some already FDA-approved for cutaneous T-cell lymphoma.
• Developing novel HDAC inhibitors with improved efficacy and broader applications remains a key research area.

Purpose of the Study:

• To explore a novel quinolone cap structure with a hydroxamic acid zinc-binding group (ZBG) for HDAC inhibition.
• To evaluate the antiproliferative and pan-HDAC inhibitory activities of newly synthesized compounds (4a-4w).

Main Methods:

• Synthesis of novel quinolone-based compounds incorporating a hydroxamic acid ZBG.
• Evaluation of pan-HDAC inhibitory and antiproliferative activities against colon (HCT-116), lung (NCI-H460), and glioblastoma (U251) cancer cell lines.
• Assessment of metabolic stability in both microsomal liver (MLM) and hepatic (HLM) fractions.

Main Results:

• The novel quinolone cap compounds demonstrated significant pan-HDAC inhibitory and antiproliferative activities.
• Introduction of heterocyclic amines in the CAP region enhanced both enzyme inhibitory and antiproliferative effects.
• Several compounds exhibited favorable metabolic stability in MLM and HLM.

Conclusions:

• The novel quinolone cap HDAC inhibitors show potent anticancer potential.
• Structural modifications, specifically the addition of heterocyclic amines, can enhance the efficacy of these compounds.
• The tested compounds represent promising candidates for further development in cancer treatment.