New Drug Research and Development Center, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Molecules. 2020 Dec 8;25(24):5779. doi: 10.3390/molecules25245779.
Herein, we sought to evaluate the contribution of the 1,3,5-triazine ring through the metformin cyclization unit to the biological activity of magnolol and honokiol-conjugates. One of the phenolic OH groups of magnolol or honokiol was replaced by a 1,3,5-triazine ring to further explore their synthesis and medicinal versatility. In this study, a robust procedure of three steps was adopted for the synthesis of magnolol and honokiol derivatives by alkylation of potassium carbonate with a 1,3,5-triazine ring. To our knowledge, this is the first report to connect one of the phenolic OH positions of magnolol or honokiol to a 1,3,5-triazine ring cyclized by metformin. The structural characterization of three new compounds was carried out via spectroscopic techniques, i.e., C NMR, H NMR, and HRMS. Surprisingly, these compounds showed no cytotoxicity against RAW 264.7 macrophages but significantly inhibited the proliferation of MCF-7 (human breast cancer cells), HepG2 (human hepatoma cells), A549 (human lung carcinoma cells), and BxPC-3 (human pancreatic carcinoma cells) tumor cell lines. Furthermore, the compounds also significantly inhibited the release of inflammatory cytokines, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in the lipopolysaccharide (LPS)-activated mouse cells (RAW 264.7). Among them, compound 2 demonstrated promising broad-spectrum antiproliferative potential with half inhibitory concentration (IC) values ranging from 5.57 to 8.74 µM and it significantly decreased caspase-3 and Bcl-2 expression in HepG2 cells. These interesting findings show that derivatization of magnolol and honokiol with 1,3,5-triazine affects and modulates their biological properties.
在此，我们试图通过将二甲双胍环化单元引入到厚朴酚和和厚朴酚缀合物中来评估 1,3,5-三嗪环的贡献。厚朴酚或和厚朴酚的一个酚羟基被 1,3,5-三嗪环取代，以进一步探索它们的合成和药用多功能性。在这项研究中，采用三步法通过碳酸钾与 1,3,5-三嗪环的烷基化反应合成厚朴酚和和厚朴酚衍生物。据我们所知，这是首次将厚朴酚或和厚朴酚的一个酚羟基连接到由二甲双胍环化的 1,3,5-三嗪环上。通过光谱技术（即 C NMR、H NMR 和 HRMS）对三个新化合物的结构进行了表征。令人惊讶的是，这些化合物对 RAW 264.7 巨噬细胞没有细胞毒性，但对 MCF-7（人乳腺癌细胞）、HepG2（人肝癌细胞）、A549（人肺癌细胞）和 BxPC-3（人胰腺癌细胞）肿瘤细胞系的增殖有显著抑制作用。此外，这些化合物还显著抑制了脂多糖（LPS）激活的小鼠细胞（RAW 264.7）中炎症细胞因子的释放，包括一氧化氮（NO）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）。其中，化合物 2 显示出有希望的广谱抗增殖潜力，其半抑制浓度（IC）值范围为 5.57 至 8.74 μM，并且显著降低了 HepG2 细胞中 caspase-3 和 Bcl-2 的表达。这些有趣的发现表明，1,3,5-三嗪对厚朴酚和和厚朴酚的衍生化影响并调节了它们的生物学特性。
