PXD101 analogs with L-phenylglycine-containing branched cap as histone deacetylase inhibitors

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Histone deacetylases (HDACs) regulate gene expression by altering chromatin structure, and their dysregulation is implicated in tumorigenesis.
• Histone deacetylase inhibitors (HDACIs) represent a promising class of anticancer agents by reactivating tumor suppressor genes.
• PXD101 (Belinostat) is an approved HDACI, and SAHA (Vorinostat) was the first approved HDACI, serving as benchmarks for novel drug development.

Purpose of the Study:

• To design, synthesize, and evaluate novel PXD101 analogs incorporating an L-phenylglycine-containing cap group as potential HDACIs.
• To assess the in vitro HDAC inhibitory and antiproliferative activities of these novel compounds.
• To compare the efficacy and isoform selectivity of the synthesized analogs against PXD101 and SAHA.

Main Methods:

• Chemical synthesis of novel PXD101 analogs featuring an L-phenylglycine-containing cap.
• In vitro evaluation of HDACs inhibitory activity for the synthesized compounds.
• Assessment of in vitro antiproliferative effects against cancer cell lines.
• Determination of HDAC isoform selectivity profiles for representative compounds.

Main Results:

• Compounds 10k, 10r, and 10s demonstrated superior HDAC inhibitory activity compared to SAHA and were comparable to PXD101.
• All six evaluated PXD101 analogs exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA.
• Compound 10s displayed an HDAC isoform selectivity profile similar to PXD101, indicating the L-phenylglycine cap did not significantly alter selectivity.

Conclusions:

• The novel L-phenylglycine-containing PXD101 analogs possess potent HDAC inhibitory properties.
• While demonstrating strong HDAC inhibition, the antiproliferative effects of these analogs are moderate, suggesting further optimization is needed.
• The structural modifications did not drastically alter the HDAC isoform selectivity profile of PXD101.