Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng 252000, PR China.
Bioorg Chem. 2022 Sep;126:105853. doi: 10.1016/j.bioorg.2022.105853. Epub 2022 May 10.
As a very important lipophilic cation, the triphenylphosphonium moiety has been extensively studied in the development of anticancer agents. In this work, we adopted 1,2,3-triazole as the linking group to prepare triphenylphosphine salt-natural triterpenoid conjugates. We chose the rarely studied natural triterpenoid allobetulin as the lead compound and prepared three 1,2,3-triazole derivatives of allobetulin by the triazolization reaction which was developed by our group. The hydroxyl group was then replaced by bromination, and the target triphenylphosphonium-linked derivative of allobetulin 5 was obtained by reacting with triphenylphosphine. The cytotoxicity screening showed that the target compound 5 displayed same antiproliferative activity against tested cancer cells as the commercial anticancer drug doxorubicin but more active than cisplatin. Further studies on the mechanism of action indicated that compound 5 could obviously induce SGC-7901 cells apoptosis through the mitochondrial pathway, inducing cell cycle arrest. Moreover, compound 5 also could reduce the expression of Vimentin and increase the expression of E-cadherin to hinder Epithelial-mesenchymal transition (EMT). Since compound 5 has excellent anticancer activity, further research and development should be done.
作为一种非常重要的亲脂性阳离子，三苯基膦部分在抗癌药物的开发中得到了广泛的研究。在这项工作中，我们采用 1,2,3-三唑作为连接基团，制备三苯基膦盐-天然三萜类缀合物。我们选择了研究较少的天然三萜类化合物白桦脂醇作为先导化合物，并通过我们小组开发的三唑化反应制备了三种白桦脂醇的 1,2,3-三唑衍生物。然后用溴取代羟基，并用三苯基膦与溴化反应得到目标三苯基膦键合的白桦脂醇衍生物 5。细胞毒性筛选表明，目标化合物 5 对测试的癌细胞表现出与商业抗癌药物阿霉素相同的增殖抑制活性，但比顺铂更活跃。对作用机制的进一步研究表明，化合物 5 可以通过线粒体途径明显诱导 SGC-7901 细胞凋亡，诱导细胞周期停滞。此外，化合物 5 还可以降低波形蛋白的表达，增加 E-钙黏蛋白的表达，从而阻止上皮-间充质转化（EMT）。由于化合物 5 具有优异的抗癌活性，应该进一步进行研究和开发。
