Regulation of gene expression by epigenetic approaches is a promising strategy both in small molecules targeted cancer therapy and in cancer immunotherapy. Concurrently, HDACs inhibitors have been developed as important epigenetic drugs, and have shown great potential in cancer therapies. As a result, the discovery of novel HDACs inhibitors containing novel functional groups to improve potency and selectivity is continuing. Amindoximes are geometric isomers of N-hyroxyamidines which are bioisosteres of hydroxamates. Since amindoxime group is capable of chelating transition metal ions including zinc ion, amindoximes should possess histone deacetylases (HDACs) inhibitory activity. In this work, we designed and synthesized a series of amindoximes with different cap motifs and linkers, while amindoxime group is used as zinc ion binding group. The amindoximes possessed submicromolar HDACs inhibitory activity and displayed noteworthy enhancement in inhibition of HDACs activity compared with hydroxamates. Amindoximes containing the distal aromatic ring in the R group and one methylene group in the linker showed good HDACs inhibitory activity. Furthermore, the amindoximes arrested HCT116 and A549 cells in G2/M phase and showed good efficacy in inducing cells death. Our work provided a proof-of-concept that amindoximes could be used as HDACs inhibitors. Since the screening of specific HDACs inhibitors may lead to the discovery of immune checkpoint expressing inhibitors, further studies describing the selectivity of amindoximes to HDACs are in progress.

Amidoximes as histone deacetylase inhibitors

255th National Meeting (2018)

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