摘要
目的设计、合成含有榄香烯结构的新型组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor, HDACI),评价其体外抗肿瘤细胞增殖活性及对组蛋白去乙酰化酶的抑制活性。方法以β-榄香烯结构作为锌离子结合型HDACI表面识别基团,分别以脂肪酸、异羟肟酸、酰胺结构片段为锌离子结合基团,设计并合成了3个含有榄香烯结构的HDACI系列。以β-榄香烯为原料,经氯代、N-烷基化、缩合、水解、Knoevenagel-Doebner反应得羧酸类目标产物,羧酸类目标产物与胺缩合得到其他目标化合物。以帕比司他为阳性对照药,采用台盼蓝拒染法,测试目标化合物对人早幼粒白血病细胞HL-60的增殖抑制活性以及对HDAC1、HDACs的抑制活性。结果与结论合成了15个未见文献报道的化合物,结构经1H-NMR和MS谱确证。体外活性评价结果显示目标化合物对HL-60细胞均表现出一定的增殖抑制作用,其中目标化合物A3、A4、B2对HL-60细胞生长抑制浓度GI50值均小于4μmol·L^(-1)。综合所有化合物对酶和肿瘤细胞的活性数据,目标化合物B2对HDAC1、HDACs的抑制以及对HL-60细胞的生长抑制均较强。
The degree of histone acetylation was regulated by histone deacetylase (HDAC) and histone acetyltransferase (HAT).In recent years,many HDAC inhibitors(HDACI) had gradually entered the market from the clinical trials.Now adays,HDACI with low toxicity and high selectivity had gradually became the focus of research.In this article,a series of novel HDACI containingβ-elemene structure were designed and synthesized,and their antitumor cell proliferation activity and histone deacetylase inhibitory activity were evaluated in vitro.Using vorinostat (SAHA) as a reference,the aromatic surface recognition group in the zinc ion-binding HDAC inhibitor was replaced withβ-elemene structure,and fatty acids,hydroxamic acids,amides were used as zinc ion binding group.β-Elemene was used as raw material,firstly.The target products of carboxylic acid were obtained through chlorination,N-alkylation,condensation,hydrolysis,Knoevenagel-Doebner reaction.And finally,target products of carboxylic acid were condensed with substituted ammonia to obtain other target compounds.The structures of 15 new compounds were confirmed by ESI-M S and1H-NM R.Then using pabitastat as a positive control drug,the trypan blue rejection method was used to test the proliferation inhibition of human promyelocytic leukemia cell HL-60,and the inhibitory activity of the target compounds on HDAC1 and HDACs was tested.The results of in vitro activity evaluation show ed that the target compounds show ed a certain grow th inhibitory effect on HL-60 cell,among which grow th inhibitory concentration GI50of three compounds A3,A4 and B2 on HL-60 cell were less than4μmol·L^(-1).When the concentrations of the compounds A2,B2 and C2 whose zinc ion binding group was hydroxamic acid were 1,10μmol·L^(-1),the inhibition of HDACs was positive correlation.Combining the enzyme and tumor cell activity data of all compounds,compound B2 had stronger enzyme inhibition on HDAC1 and HDACs and better growth inhibition on HL-60 cell.
作者
吴斐斐
王林
刘子超
包宇
张美慧
徐莉英
WU Fei-fei;WANG Lin;LIU Zi-chao;BAO Yu;ZHANG Mei-hui;XU Li-ying(Key Laboratory of Structure-Based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China;Tianjin Institute of Pharmaceutical Research,Tianjin 300462,China;Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China)
出处
《中国药物化学杂志》
CAS
CSCD
2021年第3期167-177,共11页
Chinese Journal of Medicinal Chemistry
