目的 設(shè)計(jì)并合成組蛋白去乙?；敢种苿℉DACi），并對(duì)其組蛋白去乙?；福℉DACs）抑制活性和體外抗腫瘤活性進(jìn)行研究。方法 以N-Boc-對(duì)苯二胺和辛二酸酐為起始原料，反應(yīng)制得7-（N-Boc-氨基）苯胺甲?；?，再通過(guò)胺醛縮合反應(yīng)合成HDACi；并采用HDACs試劑盒和CCK-8試劑盒測(cè)試所合成目標(biāo)化合物抑制HDACs的活性和抗腫瘤活性。結(jié)果 合成了26個(gè)新化合物，其結(jié)構(gòu)均經(jīng)過(guò)核磁共振氫譜和質(zhì)譜進(jìn)行了確證。初步的生物活性測(cè)試結(jié)果表明，所合成的目標(biāo)化合物對(duì)HDACs的抑制活性均強(qiáng)于陽(yáng)性藥物伏立諾他，并對(duì)MCF-7、PC-3、HepG2、MGC-803和KB 5種腫瘤細(xì)胞有不同程度的抑制活性，其中希夫堿含有吸電子基的化合物對(duì)HDACs的抑制活性以及抗腫瘤活性強(qiáng)于其他衍生物。尤其是4-氰基化合物11c對(duì)HDACs展現(xiàn)出了最強(qiáng)的抑制活性，是陽(yáng)性藥伏立諾他的58倍；同時(shí)，化合物11c對(duì)腫瘤細(xì)胞MCF-7、PC3、MGC-803和HepG2展現(xiàn)出了最強(qiáng)的抗腫瘤活性，其抗胃癌MGC-803甚至是陽(yáng)性藥物伏立諾他的7.2倍。結(jié)論 希夫堿是一類重要的抗腫瘤藥效團(tuán)，能夠提高HDACi的抗腫瘤活性，為今后發(fā)展新型、高效的HDACi提供了新的思路。

Objective To designe and synthesize hydroxamic acid histone deacetylase inhibitors(HDACi), and to investigate their HDAC inhibitory activities and anti-tumor activities in vitro. Methods N-(4-aminophenyl)-1,1-dimethylethyl ester and caprylic anhydride were used as starting materils to synthesize 8-((4-((tert-butoxycarbonyl)amino)phenyl)amino)-8-oxooctanoic acid. Then a series of HDACi were designed and synthesized by aldimine condensation. HDAC inhibitory activities of target compounds were evaluated by HDACs reagent kit, and their anti-tumor activities also were evaluated by CCK-8 assay. Results Twenty-six novel HDACi were synthesized and the structures were confirmed by ¹H-NMR and MS spectra. The preliminary biological results showed that these target compounds displayed potent against HDACs and significant anti-tumor activities on MCF-7, PC-3, HepG2, MGC-803, and KB cancer cells. And the inhibitors, which bore electron withdrawing group in schiff base unit, had more potent anti-HDACs and anti-tumor than other derivatives. Specifically, 4-cyano compound 11c exhibited most potent anti-HDACs, which was 58-fold more potent than vorinostat. Moreover, compound 11c showed the greatest potency against MCF-7, PC3, MGC-803, and HepG2, and which showed 7.2-fold more potent than vorinostat, against MGC-803.Conclusion Schiff base unit is a kind of important anti-tumor pharmacophore, which can enhance the anti-tumor activity of HDACi, and offer new mentality to develop novel and high-efficiency HDACi in the future.