d-Amino Acid Position Influences the Anticancer Activity of Galaxamide Analogs: An Apoptotic Mechanism Study.
d-Amino Acid Position Influences the Anticancer Activity of Galaxamide Analogs: An Apoptotic Mechanism Study.
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D-氨基酸位置影响 Galaxamide 类似物的抗癌活性：细胞凋亡机制研究
DOI：
10.3390/ijms18030544
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发表时间：
2017-03-10
影响因子：
5.6
通讯作者：
Xu S
中科院分区：
文献类型：
--
作者：
Bai D;Yu S;Zhong S;Zhao B;Qiu S;Chen J;Lunagariya J;Liao X;Xu S
Galaxamide是从Galaxaura filamentosa中提取的一种含有5个L-亮氨酸的环状五肽。Galaxamide及其类似物由于其独特的环状结构和良好的抗癌活性，其合成及其生物应用已引起人们的广泛关注。在目前的工作中，我们合成了六个Galaxamide类似物取代的l-亮氨酸与苯丙氨酸和不同的d-氨基酸的位置。针对四种体外人癌细胞系（人肝细胞（HepG 2）、人乳腺癌细胞（MCF-7）、人乳腺癌细胞（MDA-MB-435）和人宫颈癌细胞系（Hela））测试合成的Galaxamide类似物的抗癌效果。结果表明，具有不同d-氨基酸位置的Galaxamide类似物显示出不同的抗癌潜力。在位置5处含有d-氨基酸的Galaxamide类似物（类似物-6）呈现最强的抗癌活性。Analog-6可通过抑制HepG 2细胞生长于亚G1期，诱导细胞染色质浓缩和断裂，使68%的HepG 2细胞处于亚G1期，从而导致细胞早期凋亡。Analog-6对HepG 2细胞的凋亡过程中还存在一条由DNA介导的凋亡通路。
Galaxamide, an extract from Galaxaura filamentosa, is a cyclic pentapeptide containing five l-leucines. Due to the particular cyclic structure and the excellent anticancer activity, synthesis of Galaxamide and its analogs and their subsequent bio-applications have attracted great attention. In the present work, we synthesized six Galaxamide analogs by replacing one of the l-leucines with phenylalanine and varying the d-amino acid position. The anticancer effect of the synthesized Galaxamide analogs was tested against four in vitro human cancer cell lines, human hepatocellular cells (HepG2), human breast cancer cell (MCF-7), human breast adenocarcinoma cells (MDA-MB-435) and a human cervical carcinoma cell line (Hela). Results showed that Galaxamide analogs with different d-amino acid positions displayed distinct anticancer potential. The Galaxamide analog containing d-amino acid at position 5 (Analog-6) presented the strongest anticancer activity. The mechanism study revealed that Analog-6 could cause the early apoptosis of HepG2 cells by inhibiting their growth in the sub-G1 stage of the cell cycle and induce the chromatin condensation and fragmentation, which can be seen as 68% of HepG2 cells inhibited in the sub-G1 stage. Moreover, a mitochondria-mediated pathway was found to be involved in the apoptotic process of Analog-6 on HepG2 cells.