Design, synthesis and biological evaluation of shikonin thio-glycoside derivatives: new anti-tubulin agents
Design, synthesis and biological evaluation of shikonin thio-glycoside derivatives: new anti-tubulin agents
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DOI：
10.1039/c4ra08810g
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发表时间：
2014-10
期刊：
影响因子：
3.9
通讯作者：
Hongyan Lin;H. Han;Li-Fei Bai;Han‐Yue Qiu;Deyan Yin;J. Qi;Xiao-Ming Wang;H. Gu;Yong-Hua Yang-Yong-Hua
中科院分区：
文献类型：
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作者：
Hongyan Lin;H. Han;Li-Fei Bai;Han‐Yue Qiu;Deyan Yin;J. Qi;Xiao-Ming Wang;H. Gu;Yong-Hua Yang-Yong-Hua
设计合成了一系列乙酰基-β- d -硫苷修饰的紫草素衍生物，并研究了其对MG63、MCF-7、B16-F10、HepG2、MDA-231、L02、VERO和MCF-10A细胞系的增殖抑制作用。生物学研究表明，大多数单、二、三取代的紫草素衍生物对5种肿瘤细胞系具有较好的抗增殖活性，但对正常细胞的细胞毒活性低于紫草素本身。值得注意的是，与紫草素相比，IIb具有更强的抗增殖作用。对微管蛋白聚合的抑制结果表明，IIb的抗微管蛋白活性（IC50 = 4.67±0.433 μM）高于紫草素（IC50 = 16.8±0.625 μM）和秋水仙碱（IC50 = 3.83±0.424 μM）。对接模拟、共聚焦显微镜和western bolt结果进一步证实IIb可通过结合微管蛋白活性位点，抑制微管蛋白聚合，导致细胞在G2/M期阻滞，诱导细胞凋亡。
A novel series of acetyl-β-D-thio-glycoside modified shikonin derivatives were designed and synthesized and investigated for inhibition of cell proliferation against MG63, MCF-7, B16-F10, HepG2, MDA-231, L02, VERO and MCF-10A cell lines. The biological study showed that most single, di- and tri-substituted shikonin derivatives exhibited better anti-proliferative activities against the five cancer cell lines but lower cytotoxic activity against normal cells than shikonin itself. Notably, compared to shikonin, IIb displayed much stronger anti-proliferative effect among them. Furthermore, the inhibition of tubulin polymerization results indicated that IIb showed the most potent anti-tubulin activity (IC50 = 4.67 ± 0.433 μM), which was compared with shikonin (IC50 = 16.8 ± 0.625 μM) and colchicine (IC50 = 3.83 ± 0.424 μM). Docking simulation, confocal microscopy and western bolt results further confirmed that IIb can cause cell arrest in G2/M phase and induce cell apoptosis via binding to the active site of tubulin and inhibiting tubulin polymerization.