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

Chem. J. Chinese Universities ›› 2010, Vol. 31 ›› Issue (7): 1346.

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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.

Abstract

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

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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[J]. Chem. J. Chinese Universities, 2010, 31(7): 1346.

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

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