Design,Synthesis And Antitumor Activity Of N-(2-(2-nitrophenoxy) Acetoxy)-N-phenyls As Histone Deacetylase Inhibitors

The development of novel antitumor drugs based on Epigenetic regulation with a close relationship to occurrence and development of tumor plays a key role in cancer chemotherapeutics.So the histone deacetylases(HDACs)has become a key target for antitumor drugs due to the conclusive relationship between histone acetylation/deacetylation among the known epigenetic modifications and tumor.Recently,linkerless as a new class of histone deacetylase inhibitors(HDACi)with a simple structure has been focused on its significant improvement in the selectivity to the different subtype of deacetylase,as well as most of HDACi with a general pharmacophore constituted of a surface recognition domain,a linker domain,and a zinc ion binding group lack the selectivity to the different subtype of deacetylase.So we designed a series of N-(2-(2-nitrophenoxy)acetoxy)-N-phenyls as a novel kind of HDACi in order to removing the unwanted effect and improving the subtype selectivity,and introduced nitrophenoxyacetic acid as a carrier in order to improvement of the selectivity to the different subtype of deacetylase and the one to cancer cells.We synthesized 12 target compounds by reduction of nitro group in nitrobenzene/substituted nitrobenzene as the starting material,benzoylation of hydroxylamine in the reduced nitrobenzene/substituted nitrobenzene,and acylation of nitrophenoxyacetic acid and substituted hydroxylamine,which were confirmed by 1H-NMR,13C-NMR and EI-MS,and in which compound a4 with potent activity was pure more than 95%by HPLC analysis.The replication inhibition assay by MTT of cancer cell in HeLa(cervical cancer cell line),Ec109(human esophageal cancer cell line),A549(human pulmonary cell line)and Hep-G2(human hepatoma cell line)suggested that the serial of target compounds were not sensitive to HeLa and A549(IC50>300μM)cell lines,the activity of compound a4 in Ec-109(IC50<60μM)and Hep-G2(IC50<15μM)cell lines was equal to the one of the positive control drug SAHA,in which there was perspective of further study.Compound a4 arrested cancer replication in S phase of Hep-G2 cell line in the cell cycle analysis,but slightly inhibited in vitro HDACs,as was presented that the metabolite in tumor cell of Compound a4 launched the inhibition of cancer cell replication.In this paper,the target compounds performed in vitro antiproliferation of tumor cells,the HDACs inhibition.But in vivo activity,action mechanism,pharmacokinetics and so on are still pending.