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目的设计合成含过氧桥的组蛋白去乙酰化酶(HDAC)抑制剂,并考察化合物的抗肿瘤细胞增殖活性。方法以含过氧桥的胺类化合物或醇类化合物为起始原料,经缩合、水解、缩合、脱保护等4步反应合成目标化合物,同时合成了对应的非过氧桥类似物。采用MTT法测试化合物对肿瘤细胞及正常细胞的IC50值,探讨过氧桥、不同连接键方式、碳链的长度对化合物活性的影响。结果与结论合成了15个未见文献报道的全新化合物,化合物结构经氢谱、碳谱以及高分辨质谱确证;体外抗肿瘤细胞增殖活性评价表明,羟肟酸部分是活性必需基团,碳链缩短会导致活性降低,过氧桥结构对化合物的抗肿瘤细胞增殖活性影响较大,过氧桥取代基的位阻增大有利于提高化合物的活性,化合物对肿瘤细胞的选择性优于正常细胞。
Objective To design and synthesize a histone deacetylase (HDAC) inhibitor containing a peroxy bridge and investigate the anti-tumor cell proliferative activity of the compounds. Methods The target compounds were synthesized by 4 steps including condensation, hydrolysis, condensation and deprotection using the amine or alcohol containing peroxy bridge as the starting material. At the same time, the corresponding nonperoxo bridge analogs were synthesized. The IC50 values of the compounds on tumor cells and normal cells were measured by MTT assay. The effects of peroxy bridge, different linker and length of carbon chain on the activity of the compounds were investigated. RESULTS AND CONCLUSION: Fifteen novel compounds were reported. The structures of the compounds were confirmed by H-NMR, C-NMR and HR-MS. The anti-tumor activity in vitro showed that the hydroxamic acid moiety was an active essential group. Shortening will lead to decreased activity, the peroxide bridge structure on the compound anti-tumor cell proliferation activity greater peroxy bridge substituents increased sterility conducive to improve the activity of compounds, the selectivity of compounds on tumor cells than normal cells .