Magnolol and its semi-synthetic derivatives: a comprehensive review of anti-cancer mechanisms, pharmacokinetics, and future therapeutic potential

Abstract

In recent years, magnolol (MG), a natural active compound of polyphenolic nature, has garnered significant interest for its anti-cancer effects. Numerous studies conducted on cell lines and animal models have indicated a positive impact of administering drugs or semi-synthesized products derived from MG, including a decreased incidence of various cancers. This review aims to illustrate the underlying cellular and molecular basis of its actions. The article includes in-depth explanations of phytochemistry, semi-synthetic derivatives, bioavailability, pharmacokinetics, preclinical research, anti-tumor mechanisms, human clinical studies, toxicity, side effects, and safety. It also demonstrates that, in contrast to the wealth of synthetic medications, MG is highly effective against bladder, colon, gastric, skin, liver, lung, gallbladder, and prostate cancers. The findings of this review indicate that MG is a promising candidate as an anti-tumor agent, and future research should focus on developing new semi-synthetic derivative compounds with potential anti-tumor properties.

Keywords: Cancer cell growth inhibition; Low water solubility; Magnolia species; Magnolol; Natural polyphenolic compound; Semi-synthetic derivatives.

Fig. 1

Structures of magnolol, honokiol and magnolol-2-O-glucuronide

Fig. 2

Semi-synthetic magnolol derivative. A Friedel–Crafts alkylation introduces a halohydrocarbon to MG, adding an alkyl group to the benzene ring. The intermediate product undergoes deprotection in acidic conditions, and the compound is purified using potassium carbonate (K₂CO₃) and acetonitrile (MeCN). The reaction is conducted under nitrogen (N₂) at 95 °C for 3–12 h to introduce a functional group or perform a substitution

Fig. 3

Production of MG derivative via Pd-catalyzed Suzuki coupling. Alkylation with nBuLi and Br(OMe)₃ in THF yields a trisubstituted benzene. The product undergoes Suzuki coupling with Pd(PPh₃)₄ and Na₂CO₃ in DME at reflux for 6 h. The final substitution replaces OMe with OH and introduces iodine (I) at the meta position, using I₂, CAN, acetonitrile, AlCl₃, and Me₂S at room temperature

Fig. 4

MG derivatives were obtained through Williamson ether synthesis. The product from the previous reaction interacts with Na₂CO₃ and DMF, resulting in a sodium alkyloxide ion. This ion subsequently reacts with an alkyl halide, replacing the OH group with an OR group and leading to two products featuring alkyloxy groups instead of hydroxyl groups

Fig. 5

Semi-synthetic magnolol derivatives synthesized through esterification with n-propyl acid chloride (nPrCOCl) and K₂CO₃. This reaction produces both monoester and diester derivatives

Fig. 6

Synthesis of a magnolol derivative via the Mannich reaction. The Mannich reaction involves the condensation of a ketone or aldehyde, a primary amino group (such as morpholine), and an active methylene group (–CH₂–). This reaction produces a Mannich base that can subsequently react with MG, resulting in a semisynthetic MG derivative that may modify its chemical properties and applications

Fig. 7

The active site is similar to Gedalotisib (green) and Magnolol (red)

Fig. 8

Magnolol induces cell cycle arrest and apoptosis and suppresses cell growth and proliferation; it prevents angiogenesis. Magnolol acts in molecular pathways involved with anti-cancer actions, such as PI3 K/Akt/mTOR, MAPK, and NF-κB