酞嗪酮类新型免疫抑制剂的合成与活性研究  

Synthesis and immunosuppressive effects of novel phthalazine ketone derivatives

作　　者：王亚丽[1] 王庆河[1] 杨红光[1] 郝伯钧[1] 梁国栋[1] 江崇国[1] 程卯生[1] 

机构地区：[1]沈阳药科大学,基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《药学学报》2013年第10期1579-1584,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(21372157)

摘　　要：以邻苯二甲酰亚胺为原料,经选择性还原、硝化、溴代、扩环、还原、Knoevenagel和酰化反应,合成了15个未见文献报道的化合物,结构经1H NMR、HR-MS确证。以临床应用的免疫抑制剂霉酚酸(MPA)作为阳性对照药,采用小鼠体外脾细胞增殖抑制法考察了目标化合物对小鼠T细胞免疫抑制活性,对化合物7a和7h进行IMPDH酶抑制活性研究。体外活性结果显示,该系列化合物具有较好的T细胞抑制活性,其中化合物7f、7h活性最好,IC50分别为0.093μmol·L-1和0.14μmol·L-1,好于阳性对照药MPA,酶活性与细胞活性一致。A series of phthalazine ketone compounds were synthesized and the structures were confirmed by 1H NMR and HR-MS spectrum. All target compounds were obtained through 7 steps, including selective reduction, nitration, bromination, ring enlargement, reduction, Knoevenagel and acylated reaction. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and inhibitory activity of IMPDH type II in vitro, as well as their structure-activity relationship were assessed. Several compounds exhibited strong immunosuppressive properties, especially compounds 7f and 7h, with IC50 values of 0.093 μmol·L-1 and 0.14 μmol·L-1 respectively, which were superior to mycophenolic acid. The information obtained from the studies may be useful for further research on the immunosuppressive agents.

关 键 词：酞嗪酮 免疫抑制 T细胞 IMPDH 构效关系 

分 类 号：R916[医药卫生—药学]