Development of 3-hydroxycinnamamide-based HDAC inhibitors with potent in vitro and in vivo anti-tumor activity

• A new series of 3-hydroxycinnamamide-based HDACIs were synthesized.
• The series of compounds displayed pan-HDAC inhibitory activity.
• Compound 7h showed potent in vitro antiproliferative activity.
• 7h was a potent, orally active HDACI in in vivo assay.

Inhibition of histone deacetylases (HDACs) has diverse effects on cell function, such as causing differentiation, growth arrest and apoptosis in nearly all types of tumor cell lines. In our previous work, we have designed and synthesized a novel series of 4-hydroxycinnamamide-based and 3-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which, 3-hydroxycinnamamide-based HDACIs 1a–1c exhibited moderate inhibition against HDACs. In this article, we report the development of a more potent class of 3-hydroxycinnamamide-based HDACIs, compound 7o exhibited much higher pan-HDAC inhibitory activity than positive control SAHA. In addition, compound 7h showed excellent in vitro growth inhibitory activity against more than ten cell lines and induced U937 cells apoptosis in micromolar concentration. In vivo assay in U937 xenograft model identified compound 7h as a potent, orally active HDACI.

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