Friday, July 15, 2011

Chew on This - Druglike Plant Phenols

Two URI chemists inadvertently sparked a syrupy turf war earlier this year, when they announced the isolation of quebecol, a newly-identified phenolic produced from the processing of maple syrup (see WIRED and WSJ-Blogs). Sugar makers in Vermont, fiercely proud of their own product, figured the name was a concession to the study’s sponsors, the Quebec Federation of Maple Syrup Producers. The authors indicate that these compounds might have biological activity, but they don’t expand on any early guesses. I won’t take sides in this heated debate, but it’s good to see renewed public interest in healthy plant phenols. 

Phenol itself – simply a benzene ring with an “OH” attached – was first isolated from coal tars, and under its common name carbolic acid sold for wound cleaning and sterilization. This was commonplace in the early 1900s, before the many side effects of phenol overexposure (skin burns, CNS depression, respiratory distress, or coma) were fully realized.
For plants, the phenol motif forms the backbone of lignin, the “cement” which holds components of the cell wall together. Metabolites of this omnipresent polymer have evolved to serve as insecticides, fungicides, and plant pigments. In some cases, these phenolics repel herbivores such as horses and cattle, and there are many documented cases of poisoning following leaf or bark ingestion.
You may already be familiar with many common phenols as components of flavorings and herbal medicines: vanillin, eugenol (clove oil), and guaiacol, a dark note produced from roasting beans or nuts. In fact, thymol, a prominent flavor of the herb thyme, synergizes the activity of the fungicide itraconazole against several common pathogenic fungi.   It’s thought that this synergy occurs through disruption of the MAPK signaling pathway in the fungus, or by oxidative stress.
In addition to freshening breath, many chewing gums now contain magnolia bark extracts. Two biphenols, magnolol and honokiol, form the bulk of these extracts, which exhibit a range of biological activities. In gum, the compounds tackle the malodorous bacteria found between teeth after lunch. As a pure compound, honokiol shows neuroprotective, antibacterial, antiviral, and even anti-cancer activity in drug-resistant cell lines. To expedite production of honokiol analogues, several short total syntheses were recently reported (32-54% over four or five steps).  Most utilize a Suzuki-Miyaura coupling to join the biphenol core, and a final Claisen rearrangement to transfer an allyl group from oxygen to the aromatic core.
An entire post, maybe a book, could be written about the current all-star of healthy phenolics, resveratrol. Found in wine and seaweed, it has been the beneficiary of all sorts of good claims, from cardiovascular improvements to possible life extension. In fact, Sirtris Pharmaceuticals, founded in 2004, focused on resveratrol analogues as potential modulators of sirtuins, proteins known to serve multiple roles in gene transcription and caloric regulation (*Note: as reported in C&EN, the company now suggests that these analogues may bind not to the sirtuin active site, but to another site on the protein). Sirtris, later acquired by GSK, recently announced that they would cease research on resveratrol itself, and focus instead on analogues based on the core structure.
To be honest, this small collection barely scratches the surface of the phyto-powers lurking undiscovered beneath the skins of fruits, spices, and bark.  Luckily, the nomenclature faux pas can be solved… might I suggest seearrohl?

Updates (July 18) - Fixed spelling of "reservatrol", "resrvtravol", err, dangit! Thanks Lila!
(July 30, 7:02PM) - Commenter gippgig warns that the inhibition of sirtuins by resveratrol may be an artifact of the data, and may instead activate AMP-kinase. For those interested in more plant phenolics, Napoleon's Buttons [Le Couteur and Burreson, 2004] covers them in Chapters 1 & 7.


  1. Hooray for resveratrol! And for being able to comment!

  2. About time you got your own place! Looking forward to future posts and having all your stuff in one place. I know one of the authors on the Denton honokiol synthesis pretty well; I'll inform him of his new found fame!

  3. Not all plant phenols are likely to be healthy; some of these things look uncomfortably like DES.
    The interaction of resveratrol with sirtuins seems to be an artifact; In the Pipeline has covered this extensively (see GSK's Response to the Sirtuin Critics, Aug. 25, 2010). The actual mode of action appears to be activation of AMP-dependent protein kinase, a very interesting enzyme. For a good recent review of AMPK see Biochemical Society Transactions vol. 39 p. 1.

  4. Hey, thanks! You are a quite-well-informed commenter.

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