Abstract
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., 13C NMR, 1H 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 (IC50) 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.
Highlights
Magnolia officinalis is a flowering plant that is native to China, South Korea, and Japan
Based on the research of previously reported literature and our laboratory experiments, we identified that the biological activity of magnolol or honokiol could be increased to the desired level by introducing a pharmacophore into one of its phenolic OH groups and exposing the other
First,First, the the cyclization of metformin hydrochloride and methyl bromoacetate, which was catalyzed by sodium cyclization of metformin hydrochloride and methyl bromoacetate, which was catalyzed by sodium methoxide, was ethanol at 0at◦ C0for h and thethen intermediate
Summary
Magnolia officinalis is a flowering plant that is native to China, South Korea, and Japan. The root and stem bark of this plant are enriched with two bioactive constituents, magnolol and honokiol, with the IUPAC names of 1,5,50 -diallyl-2,20 -dihydroxybiphenyl and 2,5,50 -diallyl-2,40 -dihydroxybiphenyl, respectively. These compounds are the isomers of hydroxylated biphenyls [1]. Metformin is isolated from Galega officinalis (French Lilac) and is a widely prescribed medication against type 2 diabetes mellitus (T2DM). In the 1950s, its usefulness as an oral medication against hyperglycemia became widely known [8].
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