Synthesis of [Gly-1]RA-VII, [Gly-2]RA-VII, and [Gly-4]RA-VII.: Glycine-containing analogues of RA-VII, an antitumor bicyclic hexapeptide from Rubia plants
Synthesis of [Gly-1]RA-VII, [Gly-2]RA-VII, and [Gly-4]RA-VII.: Glycine-containing analogues of RA-VII, an antitumor bicyclic hexapeptide from Rubia plants
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DOI：
10.1021/jo030293p
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发表时间：
2004-03-05
影响因子：
3.6
通讯作者：
Takeya, K
中科院分区：
文献类型：
--
作者：
Hitotsuyanagi, Y;Hasuda, T;Takeya, K
本文报道了茜草属植物抗肿瘤双环六肽RA-VII（1）的三个类似物的合成。通过将1降解得到的环异酪氨酸单元连接到三种不同的含甘氨酸的四肽上，然后进行大环化，制备了三种类似物，[Gly-1]RA-VII（4）、[Gly-2]RA-VII（5）和[Gly-4]RA-VII（6），其中1中的三个丙氨酸残基之一被甘氨酸残基取代。在这三种类似物中，类似物4显示出最高的细胞毒活性。NMR研究表明，类似物4在溶液中的构象及其比例与天然肽1非常相似，表明Ala-2和Ala-4上的甲基是产生生物活性构象所必需的，而D-Ala-1上的甲基不是必需的。
Three analogues of RA-VII (1), an antitumor bicyclic hexapeptide from Rubia plants, were synthesized. Three analogues, [Gly-1]RA-VII (4), [Gly-2]RA-VII (5), and [Gly-4]RA-VII (6), in which one of the three alanine residues in 1 was replaced by a glycine residue, were prepared by linking of the cycloisodityrosine unit, obtained by degradation of 1, to three different glycine-containing tetrapeptides followed by macrocyclization. Of these three analogues, analogue 4 showed the highest cytotoxic activity. The NMR study revealed that in solution the conformer structures and their ratios of analogue 4 were very similar to those of natural peptide 1, suggesting that the methyl groups at Ala-2 and Ala-4 should be essential for producing the bioactive conformation, whereas that at D-Ala-1 is not essential.