Novel Azaborine-Based Inhibitors of Histone Deacetylases (HDACs)

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Organic Synthesis

Background:

• Aromatic rings are common in pharmaceuticals but decrease water solubility.
• Histone deacetylase inhibitors (HDACis) are important therapeutic agents.
• Improving solubility and structural diversity of HDACis is a key challenge.

Purpose of the Study:

• To explore azaborine rings as replacements for aromatic systems in HDAC inhibitors.
• To synthesize novel azaborine-containing compounds and evaluate their HDAC inhibitory activity.
• To assess the potential of azaborines for developing new therapeutic agents.

Main Methods:

• Synthesis of azaborine analogs isosteric to naphthalene and indole.
• Incorporation of azaborines as capping units in HDAC inhibitor scaffolds.
• Testing of 24 synthesized compounds for inhibitory activity against HDAC1, HDAC4, and HDAC8.

Main Results:

• Nearly 50% of the tested azaborine-containing compounds showed inhibitory activity.
• Three compounds exhibited IC50 values in the nanomolar range.
• Demonstrated successful incorporation of azaborine building blocks into HDACis.

Conclusions:

• Azaborine rings can be effectively integrated into HDAC inhibitors, leading to potent activity.
• This approach enhances structural diversity and offers a strategy to overcome patent limitations.
• Azaborine scaffolds hold promise for developing active pharmaceutical substances against various targets.