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Design, synthesis and anticancer potential of NSC-319745 hydroxamic acid derivatives as DNMT and HDAC inhibitors
- Source :
- European Journal of Medicinal Chemistry. 134:281-292
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Methyltransferase
Antineoplastic Agents
Apoptosis
Hydroxamic Acids
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line, Tumor
Neoplasms
Drug Discovery
Humans
DNA (Cytosine-5-)-Methyltransferases
Epigenetics
Cell Proliferation
Pharmacology
chemistry.chemical_classification
Hydroxamic acid
biology
Organic Chemistry
General Medicine
DNA Methylation
HDAC6
Gene Expression Regulation, Neoplastic
Histone Deacetylase Inhibitors
Molecular Docking Simulation
030104 developmental biology
Enzyme
Histone
Biochemistry
chemistry
Acetylation
Drug Design
030220 oncology & carcinogenesis
biology.protein
Drug Screening Assays, Antitumor
Pharmacophore
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....c2771ec934f986be2ff85776ea7fcabe