Development of Biphenyl-Substituted Uracil-Based Hydroxamic Acids (UBHAs) as Potent HDAC Inhibitors with...

Histone deacetylases (HDACs) regulate transcription by removing acetyl groups from lysines, and their dysregulation promotes cancer. Clinically approved HDAC inhibitors show limited isoform selectivity, toxicity, and modest efficacy in solid tumors. We therefore designed and synthesized uracil-based hydroxamic acids (UBHAs) bearing systematic cap group and linker modifications. Several compounds achieved nanomolar inhibition, particularly against HDAC6, and reduced activity toward class I isoforms. Structure-activity relationships highlight that para-substituted phenyl moieties and four-carbon linkers enhance potency. Compounds 14a and 14b emerged as lead candidates, reducing cancer cell viability at submicromolar doses while sparing noncancerous cells. In U937 cells, both promoted cell-cycle arrest, apoptosis, and H3K9 and α-tubulin acetylation, alongside modulation of apoptosis-related genes and microRNAs. In prostate cancer models, 14a inhibited AR^- and AR⁺ cell proliferation, enhanced histone and tubulin acetylation, upregulated p21, and downregulated Bcl-2. These findings identify biphenyl-substituted UBHAs as promising therapeutics and probes to dissect HDAC biology.