Honokiol

Honokiol (C18H18O2) is a biphenolic molecule present in the cones, bark, and leaves of  Magnolia grandifloris that has been used in the traditional Japanese medicine Saiboku-to as an anxiolytic, anti-thrombotic, anti-depressant, anti-emetic, and anti-bacterial. While early research on the effective compounds in traditional remedies have simply used whole magnolia bark extracts, known as houpu magnolia, recent work has identified honokiol and its structural isomer magnolol as the active compounds in magnolia bark. In the late 1990's honokiol saw a revival in western countries as a potent and highly tolerable anti-tumorigenic and neurotrophic compound.

Biological Activity
Anti-tumorigenic activities

Honokiol has shown pro-apoptotic effects in melanoma, sarcoma, myeloma, leukemia, bladder, lung, prostate, and colon cancer cell lines1-4. Honokiol inhibits phosphorylation of Akt, p44/42 mitogen-activated protein kinase (MAPK), and  src. Additionally, honokiol modulates the nuclear factor kappa beta (NfKB) activation pathway, an upstream effector of vascular endothelial growth factor (VEGF),  cyclooxygenase 2 (COX-2), and MCL1, all significant pro-angiogenic and survival factors. Honokiol induces caspase-dependent apoptosis in a TRAIL-mediated manner, and potentiates the pro-apoptotic effects of doxorubicin and other etoposides. So potent is honokiol's pro-apoptotic effects that it overcomes even notoriously drug resistant neoplasms such as multiple myeloma and chronic B-cell leukemia.

Neurotrophic Activity

Honokiol has been shown to promote neurite outgrowth and have neuroprotective effects in rat cortical neurons. Additionally, honokiol increases free cytoplasmic Ca2+ in rat cortical neurons5.

Anti-thrombolytic

Honokiol inhibits platelet aggregation in rabbits in a dose-dependent manner, and protects cultured RAEC against oxidized low density liproptein injury. Honokiol significantly increases the prostacyclin metabolite 6-keto-PGF1alpha, potentially the key factor in honokiol's anti-thrombotic activity6.

Purification
Several methods for purifying honokiol have been utilized. As honokiol exists naturally with its structural isomer magnolol, which differs from honokiol only by the position of one hydroxyl group, purification has often been limited to a HPLC or electromigration. However, methods developed in 2006 by workers in the lab of Jack L. Arbiser, took advantage of the proximity of the phenolic hydroxyl groups in magnolol, which form a protectable  diol, to generate a magnolol acetonide (Figure 1), with a subsequent simple purification via flash chromatography over silica7.

Figure 1



''Magnolol and Honokiol are normally inseparable. Honokiol is easily separable from the protected magnolol acetonide''

Synthesis
The synthesis of pure honokiol (Figure 2) involves a Pd-catalyzed Myaura-Suzuki coupling, but this synthesis has afforded only moderate yields8. An older synthetic method involves reaction of quinol-acetates with the Grignard reagent followed by claisen rearrangement9.

Figure 2



Synthetic scheme for total synthesis of honokiol utilizing Pd-catalzyed Suzuki-coupling.