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  • br Acknowledgments This research was

    2021-09-13


    Acknowledgments This research was funded by generous grants from the Singapore National Medical Research Council (NMRC CBRG grant NMRC/CBRG12Nov114 (BD)). WJC is supported by NMRC Clinician Scientist Investigator award and partly supported by a Singapore Cancer Syndicate Grant, the National Research Foundation Singapore and FSLLRY-NH2 receptor the Singapore Ministry of Education under the Research Centers of Excellence initiative. JJYY is supported by research grant NSC102-2320-B-001-007-MY3 from the Ministry of Science and Technology, Taiwan. The authors thank the NUS Drug Development Unit (http://ddu.nus.edu.sg/) for technical support with toxicity assays and Pondy Murugappan Ramanujulu for support with cellular assays.
    Histone deacetylases (HDACs) are important epigenetic enzymes involved in chromatin remodeling, thereby directly regulating the transcription of various genes by removing the acetyl group of histone lysines [,]. Recent studies indicate that HDAC inhibitors (HDACi) display remarkable therapeutic efficacy against certain cancers [, , ]. Of the various developed HDAC inhibitors [, , , ], five have been approved for the treatment of refractory cutaneous T-cell lymphoma (CTCL) (suberoylanilide hydroxamic FSLLRY-NH2 receptor (SAHA) and romidepsin), or peripheral T-cell lymphoma (PTCL) (romidepsin, belinostat, and chidamide), or for use in patients with recurrent multiple myeloma (panobinostat) [,]. Most HDAC inhibitors, including SAHA, belinostat, and panobinostat, share essential pharmacophoric structural features: a cap group interacting with the surface of the enzyme, a zinc-binding group (ZBG), such as a hydroxamic acid chelating group, chelating the zinc atom in the HDAC catalytic site, and a linker with the proper length to connect them []. Their flexible structure-activity relationship leads to the easy connection of HDAC inhibitors with a variety of other anti-cancer core scaffolds, promoting the extensive development of dual-target HDACi drugs, which possess enhanced anticancer efficacy [,]. Despite the reports on the effects of suppressing tumor cell proliferation of these developed hybrids, their underlying molecular mechanisms require additional study. In recent decades, significant advances in omics technology have enabled high-throughput monitoring of multiple molecular and biological processes, making it a powerful platform to explore the action mechanisms of drugs [,]. As major carriers and function performers of cellular activities, proteins carry a wealth of biological information [], allowing proteomics to provide important insights into the mechanism of drug action through a comprehensive analysis of protein alterations [, , ]. Apart from HDAC, DNA methyltransferase (DNMT) is another important epigenetic target in anticancer drug development. Two DNMT inhibitors, 5-azacytidine and decitabine, were approved by FDA in 2004 and 2006, respectively. Previous studies have shown that the combination of DNMTi and HDACi displayed improved potency in inhibiting the development of multiple types of tumor [, , , ]. Focusing on the development of and having successfully synthesized multitargeted antitumor agents [, , , ], our group recently synthesized a series of hydroxamic acid derivatives as DNMT and HDAC dual target inhibitors. Among them, compound (A) displayed potent HDAC inhibitory activity against HDAC1 and HDAC6 with IC values of 2.40 nmol/L and 4.83 nmol/L, respectively, less than that of the reference compound SAHA (HDAC1: IC = 11.11 nmol/L; HDAC6: IC = 7.76 nmol/L), and exhibited a 44.48% inhibition rate on DNMT1 at 50 μmol/L in the H-3-labeled radioactive methylation assay [] (Table S1 in Supporting information). The cytotoxicity assay results (Table S2 in Supporting information) revealed that possesses substantial antiproliferative activity against multiple tumor cells at low concentrations and could effectively suppress the proliferation of U937 cells with an IC value of 1.30 μmol/L at 72 h.