Hydrazide-Based\nClass I Selective HDAC Inhibitors\nCompletely Reverse Chemoresistance Synergistically in Platinum-Resistant\nSolid Cancer Cells

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