放线菌素D新类似物的设计、合成与体外抗肿瘤活性  

Design,Synthesis and in vitro Antitumor Activity of Novel Actinomycin D Analogs

作　　者：张邦治[1,2] 王凯荣[2] 王则周[1] 李欣檑[1] 王小丽[1] 倪京满[3] 

机构地区：[1]兰州大学生命科学学院,兰州730000 [2]甘肃省新药临床前研究重点实验室,兰州730000 [3]兰州大学药学院,兰州730000

出　　处：《高等学校化学学报》2010年第7期1346-1352,共7页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:30940090);教育部博士点基金新教师项目(批准号:20070730052);兰州大学交叉学科青年创新研究基金(批准号:LZU200509);中央高校基本科研业务费专项资金(批准号:lzujbky-2009-40)资助

摘　　要：为了提高临床抗肿瘤药物放线菌素D(AMD)的抗肿瘤效果和治疗指数,在AMD构效关系研究基础上,设计全合成了包括9个新类似物在内的两类共13个AMD类似物.保持环肽2位D-Val不变,环肽5位分别用Sar,D-Me-Leu和Me-Ile等氨基酸替换以改变侧链基团长度,合成了类似物8b～8e;以环肽2位D-Phe替换的低毒性类似物[D-Phe2]2AMD为基础,在环肽5位进行氨基酸替换,改变侧链基团长度和空间指向,并引入芳香族氨基酸等,合成了类似物8f～8m.优化了类似物的合成中的反应条件,提高了五肽环化产率,避免了消旋产物的生成.所有类似物经[α]D,1HNMR和高分辨质谱表征后,采用MTT法进行了体外抗肿瘤活性筛选,结果表明,保留环肽2位D-Val及延长5位氨基酸侧链基团能显著提高类似物的抗肿瘤活性,而2位D-Phe替换后类似物的抗肿瘤活性普遍下降.Actinomycin D（ AMD） ,containing a planar phenoxazone ring and two cyclic pentapeptides,is well known for its specific inhibition of DNA transcription and the clinical use in the treatment of highly malignant tumors. On the basis of the crystal structure of the DNA-AMD complex and structure-activity relationships of AMD analogs,two types of AMD analogs were designed and total chemically synthesized. Three novel analogs were designed to study the effect of lengthening and shortening the side chains of L-Me-Val,in which amino acid replacements were made by D-Me-Leu,Me-Ile and Sar,discussed with L-Me-Leu analog which has been reported. A serial [D-Phe2 ]AMD analogs in which L-Me-Val was replaced with Sar,D-Me-Ala, D-Me-Val,L-Me-Leu,D-Me-Leu,Me-Ile,L-Me-Phe,D-Me-Phe were designed. All analogs were prepared from C terminal to N terminal to form linear pentapeptides,then cyclized,and condensed with BMNBCA,followed by catalytic reduction,controlled oxidation and purification,and afforded as red solid. The spectrum data of all analogs including HR-MS,1H NMR and [α]D were given. In vitro antitumor effects of all analogs against SGC-7901,BEL-7402,TB,HepG-2 and MCF-7 cell lines were tested. The results show that analogs retaining D-Val2 but with long side chains at the 5th position play more powerful in vitro antitumor activity than AMD itself,though the in vitro antitumor activities of [D-Phe2]AMD analogs are generally reduced.

关 键 词：放线菌素D 类似物 全合成 体外抗肿瘤 

分 类 号：O629.72[理学—有机化学]