Background: Annonaceous acetogenins (ACGs) are secondary metabolites produced by the Annonaceae family and display potent anticancer activity against various cancer cell lines. Squamocin and bullatacin are two examples of ACGs that show promising antitumor activity; however, preclinical data are not sufficient partly due to their being highly lipophilic and poorly soluble in water. These compounds also display high toxicity to normal cells. Due to these disadvantageous properties, the therapeutic potential of squamocin and bullatacin as antitumor agents has not been fully evaluated.
Methods: In order to enhance their water solubility and potentially improve their cancer targeting, squamocin and bullatacin were conjugated to a glucose or galactose to yield glycosylated derivatives by direct glycosylation or the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction (the click reaction). The synthesized compounds were evaluated for their anticancer property against HeLa, A549 and HepG2 cancer cell lines using MTT assay.
Results: Nine glycosyl derivatives were synthesized and structurally characterized. Most of them show comparable in vitro cytotoxicity against HeLa, A549 and HepG2 cancer cell lines as their parent compounds squamocin and bullatacin. It appears that the type of sugar residue (glucose or galactose), the position at which the sugar residue is attached, and whether or not a linking spacer is present do not affect the potency of these derivatives much. The solubility of galactosylated squamocin 13 in phosphate buffer saline (PBS, pH = 7) is greatly improved (1.37 mg/mL) in comparison to squamocin (not detected in PBS).
Conclusion: The conjugation of a glucose or galactose to squamocin and bullatacin yields glycosyl derivatives with similar level of anticancer activity in tested cell lines. Further studies are needed to demonstrate whether or not these compounds show reduced toxicity to normal cells and their therapeutic potential as antitumor agents.



中文翻译：

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番荔枝素糖缀合物的合成及细胞毒特性

背景：番荔枝内酯（ACGs）是番荔枝科产生的次生代谢产物，对各种癌细胞系表现出有效的抗癌活性。Squamocin 和 Bullatacin 是显示出有希望的抗肿瘤活性的 ACG 的两个例子。然而，临床前数据并不充分，部分原因是它们具有高度亲脂性且难溶于水。这些化合物对正常细胞也表现出高毒性。由于这些不利的特性，鳞甲霉素和bulatacin作为抗肿瘤剂的治疗潜力尚未得到充分评估。
方法：为了提高它们的水溶性并潜在地改善它们的癌症靶向性，squamocin 和 Bullatacin 与葡萄糖或半乳糖缀合，通过直接糖基化或 Cu(I) 催化的叠氮化物-炔烃 1,3-偶极环加成 (CuAAC) 产生糖基化衍生物) 反应（点击反应）。使用 MTT 测定法评估合成的化合物对 HeLa、A549 和 HepG2 癌细胞系的抗癌特性。
结果：合成了九种糖基衍生物并对其进行了结构表征。它们中的大多数在体外对 HeLa、A549 和 HepG2 癌细胞系显示出与其母体化合物 squamocin 和 Bullatacin 相当的细胞毒性。似乎糖残基的类型（葡萄糖或半乳糖）、糖残基的连接位置以及是否存在连接间隔物对这些衍生物的效力影响不大。与 squamocin（在 PBS 中未检测到）相比，半乳糖基化 squamocin 13在磷酸盐缓冲盐水（PBS，pH = 7）中的溶解度大大提高（1.37 mg/mL）。
结论：葡萄糖或半乳糖与 squamocin 和 Bullatacin 的结合在测试的细胞系中产生具有相似抗癌活性水平的糖基衍生物。需要进一步的研究来证明这些化合物是否显示出对正常细胞的毒性降低以及它们作为抗肿瘤剂的治疗潜力。