[MPWG] Re: My chemical interpretation of parthenolide

[Bob Beyfuss]

Hi
I shall forward your request to the medicinal plants working group. To be 
honest I don't understand the chemistry at all but I am sure others on this 
list serve do.
Bob
At 01:33 PM 2/22/2005 -0800, you wrote:
>Bob,
>
>I am the organic chemist who emailed you a few months ago regarding my 
>experience with spearmint as migraine prophylaxis. Thank you for 
>submitting my story to the Google Search; I received a couple of inquiries.
>
>While studying natural antimigraine remedies, some of Dennis Awang's 
>articles about parthenolide (e.g.: Parthenocide: The demise of a facile 
>theory of feverfew activity, J. of Herbs, Spices and Medicinal Plants, 
>5(4), 1998, 95-98 and his recent comments that appeared in HerbalGram:65, 
>36-37) surfaced and caused me to study that component of feverfew.  I 
>emailed my chemcial interpretation of that substance to Mark Blumenthal of 
>ABC and indirectly to Awang (as I do not have his email address), and 
>subsequently to Patricia deAngelis. I received nothing from anyone.
>
>Below is my chemical interpretation of parthenolide. I wonder if you think 
>it is worthy of placing it in the Google Search? I certainly would like 
>some feedback.   Please let me know.
>
>
>The recent comments indicating that parthenolide may not the active 
>constituent in feverfew caught my interest and curiosity.
>
>Considerable animal studies have been done on parthenolide for its 
>anti-inflammatory activity and its ability to inhibit the Nuclear Factor 
>kappaB (NF-kB), a molecular biology term that "it is a transcription 
>factor that mediates the _expression of genes necessary for the cell to 
>fight inflammation."  Accordingly, scientists, e.g. Dr. M. A. Moskowitz of 
>Harvard Medical School and Mass. Gen. Hospital suggests that "blockade of 
>NF-kB activity provides a novel transcriptional target for the development 
>of anitmigraine drugs." (M.A. Moskowitz et al.: NF-kB as a molecular 
>target for migraine therapy; Ann Neurol. 2002; 51: 507-516).
>
>The activity of parthenolide and similar sesquiterpene lactones is 
>primarily due to the exocyclic methylene moiety as a part of alpha, 
>beta-unsaturated lactone.  There is a proposed mechanism for degradation 
>of parthenolide:
>
>In addition to its being an alpha-beta-unsaturated lactone, parthenolide 
>has a fairly reactive epoxide ring, which can be opened by proton followed 
>by transannular cyclization and by attacks of sulphydryl groups in protein 
>(e.g. cysteine), resulting in an entirely different sesquiterpene lactone. 
>(Paul M. Dewick's "Medicinal Natural Products, a Biosynthetic Approach," 
>2nd ed., 2002, Wiley, p. 195).  This molecule, that is irreversibly bound 
>to protein, no longer has the alpha-methylene-gamma-lactone moiety.
>
>Indeed, when the exocyclic methylene group of parthenolide is reduced, 
>i.e. no more unsaturation, this "reduced parthenolide" no longer inhibits 
>the NF-kB activation. (Kwok, Crews, C., et al.: The anti-inflammatory 
>natural product parthenolide from the medicinal herb feverfew directly 
>binds to and inhibits IkB kinase; Chemistry & Biology 8 (2001) 759-766).
>
>It appears that parthenolide itself might be the active constituent in 
>feverfew.  However, the degraded molecule no longer has its 
>effect.  Perhaps it is due to its degradation, as a consequence of plant 
>thiols attacking parthenolide, that several commercial preparations of 
>feverfew have been shown to contain little parthenolide on storage. (P. Dewick)
>
>It is certainly important to have standardized QC on feverfew 
>preparations. Several articles indicate using HPLC (High Performance 
>Liquid Chromotography). I think perhaps UV-VIS might work as well, as 
>parthenolide has a distinct peak in the UV region.
>
>The above is my chemical interpretation, being new to the feverfew area. I 
>would like inputs and comments.
>
>Marjorie Nieh
>
>
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