Hydrazide-Based Class I Selective HDAC Inhibitors Completely Reverse Chemoresistance Synergistically in Platinum-Resistant Solid Cancer Cells

In this work, we have synthesized a set of peptoid-based histone deacetylase inhibitors (HDACi) with a substituted hydrazide moiety as zinc-binding group. Subsequently, all compounds were evaluated in biochemical HDAC inhibition assays and for their antiproliferative activity against native and cisplatin-resistant cancer cell lines. The hydrazide derivatives with a propyl or butyl substituent (compounds <b>5</b> and <b>6</b>) emerged as the most potent class I HDAC selective inhibitors (HDAC1-3). Further, compounds <b>5</b> and <b>6</b> outperformed entinostat in cytotoxicity assays and were able to reverse chemoresistance in cisplatin-resistant A2780 (ovarian) and Cal27 (head-neck) cancer cell lines. Moreover, the hydrazide derivatives <b>5</b> and <b>6</b> showed strong synergism with cisplatin (combination indices <0.2), again outperforming entinostat, and increased DNA damage, p21, and pro-apoptotic BIM expression, leading to caspase-mediated apoptosis and cell death. Thus, compounds <b>5</b> and <b>6</b> represent promising lead structures for developing new HDACi capable of reversing chemoresistance in cisplatin resistant cancer cells.