文档介绍：bretastatin A-4类似物的设计、合成与抗肿瘤药物活性
单媛媛1,刘红雁2,刘兆鹏1*
(1山东大学药学院,山东济南,250012;2招远市中医院,山东招远,265400)
摘要:目的设计、bertastatin A-4类似物,研究其抗肿瘤活性。方法采用环状化合物构象限制的策略,结合磺酰胺类结构片段的生物、化学特点,bertastatin A-4类似物;以N-取代邻甲苯磺酰胺为原料,通过邻位金属化作用,与芳香醛偶合;在利用我们开发的、由三甲基硅氯/NaI/乙腈试剂诱导的新型环合反应,合成一系列构象限制的CA-4类似物;通过SRB(磺酰罗丹明B)显色法,研究所合成的化合物对正常乳腺(MCF12A)细胞、人乳腺癌MCF7与耐药乳腺癌NCI/ADR-RES细胞生长的影响。结果设计、合成了7个新型的苯并磺内酰胺类化合物,其结构经核磁共振氢谱及质谱确定;部分化合物体外细胞生长抑制活性试验表明,化合物4d对人乳腺癌MCF7具有较高的选择性,而对正常乳腺细胞没有影响。结论:新型苯并磺内酰胺类CA-4类似物对人乳腺癌细胞有抑制活性和选择性,值得进一步研究。
关键词:bertastatin A-4,抗肿瘤,活性研究
Design, synthesis, and antitumor activity studies of bertastatin A-4 analogues
Shan Yuan-yuan1, Liu Hong-yan2, Liu Zhao-peng1*
(1School of Pharmaceutical Sciences, Shandong University, Ji’nan 250012; Zhaoyuan Chinese Medical Hospital, Zhaoyuan 265400)
ABSTRACT: OBJECTIVE Design and synthesis of a series of bertastatin A-4 analogues and study their inhibitory activities towards tumor cell growth. METHODS Based on the structure-activity relationship studies bertastatin A-4 derivatives, bining the biological characteristics of benzenesulfonamide pharmacophore, a series of novel conformationally restricted CA-4 analogues were designed. The benzosultams were synthesized from N-arylsubstituted benzenesulfonamides via ortho-mettalation, coupling with aryl aldehedes, oxidation and cyclization mediated by our TMSCl-NaI- reagent system. The inhibition of cell growth of some of