Discovery of Multi-target Anticancer Agents Based on HDAC Inhibitor MS-275 and 5-FU

Area of Science:

• Medicinal Chemistry
• Cancer Therapeutics
• Molecular Pharmacology

Background:

• Histone deacetylases (HDACs) inhibitors are promising cancer therapeutics.
• Combining HDAC inhibitors with cytotoxic agents like 5-fluorouracil (5-FU) demonstrates synergistic anticancer effects.
• Developing single-molecule agents with dual bioactivity is a novel therapeutic strategy.

Purpose of the Study:

• To design and synthesize novel bivalent compounds integrating HDAC inhibition and 5-FU cytotoxicity.
• To evaluate the dual-acting compounds for their ability to inhibit HDACs and inhibit cancer cell proliferation.

Main Methods:

• Synthesis of novel dual-acting compounds by conjugating MS-275 fragments with 5-FU.
• Assessment of HDAC inhibition activity of the synthesized compounds.
• Evaluation of antiproliferative activity against a panel of six cancer cell lines.

Main Results:

• The synthesized compounds, specifically 9a and 9b, exhibited comparable HDAC inhibition to the clinical HDAC inhibitor MS-275.
• Compounds 9a and 9b demonstrated moderate antiproliferative activity across the tested cancer cell lines.
• The dual-acting molecular architecture was successfully achieved.

Conclusions:

• The novel dual-acting compounds possess both HDAC inhibitory and antiproliferative properties.
• These compounds represent a promising new class of potential cancer therapeutics.
• Further investigation into these bivalent agents could lead to advanced cancer treatment strategies.