Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• Histone deacetylase inhibitors (HDACi) show therapeutic potential for neurodegeneration, cancer, and rare diseases.
• HDAC6 is a specific isoform implicated in various cellular processes relevant to disease.

Purpose of the Study:

• To design and synthesize novel spiroindoline-based inhibitors selective for the HDAC6 isoform.
• To identify potent and selective HDAC6 inhibitors for potential therapeutic applications.

Main Methods:

• X-ray crystallography was used to guide the structure-based design of inhibitors.
• Synthesis of a series of spiroindoline derivatives.
• In vitro biological assays were performed to evaluate inhibitory activity, selectivity, and antiproliferative effects.

Main Results:

• Compound 6j emerged as the most potent and selective inhibitor of human HDAC6 (hHDAC6).
• Compounds 6b, 6h, and 6j exhibited significant antiproliferative activity against various cancer cell lines.
• Western blotting confirmed increased tubulin acetylation and PARP cleavage, indicating apoptosis induction.
• Compound 6j demonstrated HDAC6-dependent inhibition of pSTAT3 phosphorylation.

Conclusions:

• Spiroindoline derivatives represent a promising scaffold for developing selective HDAC6 inhibitors.
• Compound 6j warrants further investigation as a potential therapeutic agent for cancers and other HDAC6-related disorders.