Synthesis, Characterization and Biological Evaluation of Magnolol and Honokiol Derivatives with 1,3,5-Triazine of Metformin Cyclization

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.

Honokiol inhibits the growth of hormone-resistant breast cancer cells: its promising effect in combination with metformin

“…A significant decrease in the expression of ERα and the anti-apoptotic protein Bcl-2 was found in resistant cells treated with the combination of metformin and honokiol. Interestingly, approaches to synthesize honokiol derivatives with 1,3,5-triazine of metformin cyclization have been described ( 51 ); the obtained derivatives were active against tumor cells. Compound 2 (3,5′-diallyl-2′- ((4-amino-6- (dimethylamino)-1,3,5-triazin-2-yl) methoxy)-1,1′-biphenyl]-4-ol) demonstrated a promising antiproliferative effect with IC 50 values ranging from 5.6 to 8.7 μΜ, and it significantly decreased caspase-3 and Bcl-2 expression in HepG2 cells.…”

Research Progress on the Structural Modification of Magnolol and Honokiol and the Biological Activities of Their Derivatives

“…Compound 48 exhibited broad-spectrum antiproliferative activity with IC50 values of 5.57 ~8.74 μM, significantly decreasing the expression of caspase-3 and Bcl-2 in HepG2 cells. [39] Additionally, the hydroxy groups of magnolol and honokiol were modified with ester, hydrazide, and nitrogen-containing heterocyclic 1, 3,4-oxadiazole groups (Scheme 17). As a result, the cytotoxicity of all of the derivatives was lower than that of the original parts.…”

“…Additionally, in lipopolysaccharide‐activated macrophages, these compounds greatly reduced the production of inflammatory cytokines such as NO, TNF‐ ɑ , and IL‐1 β . Compound 48 exhibited broad‐spectrum antiproliferative activity with IC50 values of 5.57∼8.74 μM, significantly decreasing the expression of caspase‐3 and Bcl‐2 in HepG2 cells [39] . Additionally, the hydroxy groups of magnolol and honokiol were modified with ester, hydrazide, and nitrogen‐containing heterocyclic 1, 3,4‐oxadiazole groups (Scheme 17).…”

Synthesis, Quality Control and Preliminary Activity Evaluation of a New Compound HM475

“…At present, most of the structural modifications of active ingredients or compounds of traditional Chinese medicines are mainly to introduce hydrophilic or lipophilic small molecular fragments into their original structures [24][25][26]. The multi-nuclear molecule design is to connect the active "natural mononuclear molecules" in traditional Chinese medicine to form multi-nuclear molecules with multiple core functions by artificial splicing to enhance the efficacy of drugs, increasing the drug function target and symptomatic treatment [27,28]. This multi-nuclear molecule not only has the characteristics of a single "natural mononuclear molecule", but also has the characteristics of multiple "natural mononuclear molecules", so that the new compound formed can remain its biological activity and improve the shortcomings of the original ingredient, even increasing its activity [29,30].…”