放线菌素D新类似物的设计、合成与体外抗肿瘤活性

高等学校化学学报 ›› 2010, Vol. 31 ›› Issue (7): 1346.

放线菌素D新类似物的设计、合成与体外抗肿瘤活性

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

1. 兰州大学生命科学学院,
2. 甘肃省新药临床前研究重点实验室,
3. 药学院, 兰州 730000

收稿日期:2009-11-06 出版日期:2010-07-10 发布日期:2010-07-10
通讯作者: 张邦治, 男, 博士, 讲师, 主要从事多肽生物化学与药物化学研究. E-mail: zhangbz@lzu.edu.cn
基金资助:
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)和中央高校基本科研业务费专项资金(批准号: lzujbky-2009-40)资助.

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

ZHANG Bang-Zhi^1,2*, WANG Kai-Rong², WANG Ze-Zhou¹, LI Xin-Lei¹, WANG Xiao-Li¹, NI Jing-Man³

1. School of Life Sciences,
2. Key Laboratory of Preclinical Study for New Drugs of Gansu Province,
3. School of Pharmaceutical, Lanzhou University, Lanzhou 730000, China

Received:2009-11-06 Online:2010-07-10 Published:2010-07-10
Contact: ZHANG Bang-Zhi. E-mail: zhangbz@lzu.edu.cn
Supported by:
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)和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/Abstract

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, ¹H NMR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.

关键词: 放线菌素D; 类似物; 全合成; 体外抗肿瘤

Abstract:

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.

Key words: Actinomycin D; Analog; Total Chemical synthesis; Antitumor activity

TrendMD:

张邦治, 王凯荣, 王则周, 李欣檑, 王小丽, 倪京满. 放线菌素D新类似物的设计、合成与体外抗肿瘤活性. 高等学校化学学报, 2010, 31(7): 1346.

ZHANG Bang-Zhi*, WANG Kai-Rong, WANG Ze-Zhou, LI Xin-Lei, WANG Xiao-Li, .... Design, Synthesis and in vitro Antitumor Activity of Novel Actinomycin D Analogs. Chem. J. Chinese Universities, 2010, 31(7): 1346.

参考文献

[1]National Committee of Pharmacopoeia(国家药典委员会). Chinese Pharmacopoeia 2005, Part Ⅱ(中国药典, 2005版, 二部)[M], Beijing: Chemical Industry Press, 2005: 355—356
[2]Farber S., D′Angio G., Evans A., Mitus A.. J. Urol.[J], 2002, 168(6): 2560—2563
[3]Osathanondh R., Goldstein D. P., Pastorfide G. B.. Cancer[J], 1975, 36(3): 863—866
[4]Matsui H., Suzuka K., Iitsuka Y., Yamazawa K., Tanaka N., Mitsuhashi A., Seki K., Sekiya S.. Cancer[J], 2002, 95(5): 1051—1054
[5]Newlands E. S., Mulholland P. J., Holden L., Seckl M. J., Rustin G. J.. J. Clin. Oncol.[J], 2000, 18(4): 854—859
[6]Limpongsanurak S.. J. Reprod. Med.[J], 2001, 46(2): 110—116
[7]Kamitori S., Takusagawa F.. J. Mol. Biol.[J], 1992, 225(2): 445—456
[8]Chu W. H., Shinomiya M., Kamitori K. Y., Kamitori S., Carlson R. G., Weaver R. F., Takusagawa F.. J. Am. Chem. Soc.[J], 1994, 116(18): 7971—7982
[9]Takusagawa F., Carlson R. G., Weaver R. F.. Bioorg. Med. Chem.[J], 2001, 9(3): 719—725
[10]NI Jing-Man(倪京满), WANG Rui(王锐), JIA Zheng-Ping(贾正平), PAN Xin-Fu(潘鑫复), HU Xiao-Yu(胡晓愚). Chem. J. Chinese Universities(高等学校化学学报)[J], 1998, 19(2): 243—245
[11]DONG Shou-Liang(董守良), NI Jing-Man(倪京满), WANG Qin(王勤), WANG Rui(王锐). J. Lanzhou University(兰州大学学报)[J], 1998, 34(1): 137—138
[12]NI Jing-Man(倪京满), YANG Xiao-Wu(杨晓武), PAN Xin-Fu(潘鑫复). J. Lanzhou University(兰州大学学报)[J], 2002, 38(3): 87—89
[13]Mauger A. B., Stuart O. A., Katz E.. J. Med. Chem.[J], 1991, 34(4): 1297—1301
[14]Takusagawa F., Wen L., Chu W. H., Li Q., Takusagawa K. T., Carlson R. G., Weaver R. F.. Biochemistry[J], 1996, 35(40): 13240—13249
[15]Shinomiya M., Chu W. H., Carlson R. G., Weaver R. F., Takusagawa F.. Biochemistry[J], 1995, 34(26): 8481—8491
[16]ZHANG Bang-Zhi(张邦治), WANG Ze-Zhou(王则周), WANG Xiao-Li(王小丽), LI Xin-Lei(李欣檑), NI Jing-Man(倪京满), WANG Rui(王锐). Chem. J. Chinese Universities(高等学校化学学报)[J], 2004, 25(10): 1857—1859
[17]Neises B., Steglich W.. Angew. Chem. Int. Ed.[J], 1978, 17(7): 522—524
[18]Chu W. H., Kamitori S., Shinomiya M., Carlson R. G., Takusagawa F.. J. Am. Chem. Soc.[J], 1994, 116(6): 2243—2253
[19]HUANG Wei-De(黄惟德), CHEN Chang-Qing(陈常庆). Peptide Synthesis(多肽合成)[M], Beijing: Science Press, 1985: 105
[20]Perlman D.(Eds.). Structure-activity Relationships Among the Semisynthetic Antibiotics[M], New York: Academic Press, 1977: 427—529
[21]Schfer M., Sheldrick G. M., Bahner I., Lackner H.. Angew. Chem. Int. Ed.[J], 1998, 37(17): 2381—2384