Design, synthesis and anticancer potential of NSC-319745 hydroxamic acid derivatives as DNMT and HDAC inhibitors

• Published in: European journal of medicinal chemistry 2017-07, Vol.134, p.281-292
• Main Authors: Yuan, Zigao, Sun, Qinsheng, Li, Dan, Miao, Shuangshuang, Chen, Shaopeng, Song, Lu, Gao, Chunmei, Chen, Yuzong, Tan, Chunyan, Jiang, Yuyang
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor bioactivity; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation - drug effects; DNMT; Drug Design; Drug Screening Assays, Antitumor; Epigenetic targets; Gene Expression Regulation, Neoplastic - drug effects; HDAC; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Molecular Docking Simulation; Multi-target; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.04.017

DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are important epigenetic targets during anticancer drug development. Recent study indicates that DNMT inhibitors and HDAC inhibitors display synergistic effects in certain cancers, therefore, development of molecules targeting both DNMT and HDAC is of therapeutic advantage against these cancers. Based on the structure of DNMT inhibitor NSC-319745 and the pharmacophore characteristics of HDAC inhibitors, a series of hydroxamic acid derivatives of NSC-319745 were designed and synthesized as DNMT and HDAC multifunctional inhibitors. Most compounds displayed potential DNMT inhibitory potency and potent HDAC inhibitory activity, especially compound 15a showed much better DNMT1 inhibitory potency than NSC-319745, and inhibited HDAC1, HDAC6 with IC50 values of 57, 17 nM, respectively. Furthermore, the synthesized compounds exhibited significant cytotoxicity against human cancer cells K562 and U937. Further mechanistic studies demonstrated that 15a treatment in U937 increased histones H3K9 and H4K8 acetylation, prompted P16 CpG islands demethylation and upregulated P16 expression, regulated apoptosis-related protein expression on the cellular level and induced remarkable U937 apoptosis. Moreover, genotoxicity of representative compounds was evaluated. In summary, our study provided a practical drug design strategy targeting multiple enzymes, and 15a represents a novel and promising lead compound for the development of novel epigenetic inhibitors as antitumor agents. [Display omitted] •Compounds inhibiting DNMT and HDAC concurrently were designed and synthesized.•Hydroxamic acid derivatives of NSC-319745 were evaluated as antitumor agents.•15a led to demethylation and reexpression of tumor suppressor gene P16.•15a prompted histones H3K9 and H4K8 hyperacetylation.•15a induced remarkable apoptosis of U937 cells in a dose-dependent manner.