Praziquantel Update January 25 2011

25 Jan
Published by MatTodd

The resolution of PZQ via PZQamine is working very nicely on a gram scale. We're still tweaking and improving it. For example the initial resolving agent identified by Syncom, dianisoyl tartaric acid, can be replaced by dibenzoyl tartaric acid. The latter is easier to purify, is less expensive (to buy and probably to make) and gives the opposite (desired!) enantiomer of PZQamine in the solid. The resolving agent can also be easily recycled in good yield. We are hoping to recruit a company to help with the demonstration of this resolution on a 500 g scale, which will generate enough material for studies on formulation and will assist with a determination of likely cost, among other things.

 
Certainly if anyone would like to use the procedure (paper in progress) to generate enantiopure PZQ, please go ahead. It's very simple to do, relying as it does on crystallizations and not chromatography. Alternatively if anyone would like samples of enantiopure PZQ, let us know (ideally on this site). We're also going to pilot an educational project in which undergraduates can help with optimizing this process. If you're involved with undergraduate chemistry labs, and you'd like to have your students do something constructive in open science, that might result in a paper, let me know and I can mail you an outline of the project as it stands at the moment.

 
Another approach that's being looked at for the generation of enantiopure PZQ is the asymmetric hydrogenation of the PZQ enamide. DSM have just released the data from their latest screen of 48 ligands (bottom of this post), reinforcing that this is a tough reaction to do. Kudos to DSM for this work, and for releasing all the primary data for these negative results, which are crucial. Three ligands gave what might be a little bit of conversion, but otherwise everything tried to date has given little. Still the only reported lead was from Development Chemicals' hydrogenation of the analogous enamide where cyclohexanoyl was replaced with benzoyl. This cyclohexanoyl enamide is clearly the Chuck Norris of substrates; besides actually finding a ligand that works, the ligand will need to be used with a low loading to make this a commercially-viable process. Of course that's what makes it so interesting. We're still looking for people with in-house ligands who might want to try out this substrate – we'll send you some in the mail. If anyone has an idea why the cyclohexanoyl/benzoyl shift makes a difference to the outcome, feel free to speculate. I remember reading in a patent that the benzoyl compound itself is active for schisto. Why aren't we using that as the drug instead of PZQ, again?

 
For the past two months I've been travelling, both vacation and work. I was able to talk about this project at a variety of places in South Africa (Cape Town and Johannesburg), the UK (Cambridge, UCL, Southampton and at the Nature offices in London) and in Geneva (where I finally had the enormous pleasure of meeting this project's WHO/TDR champion, Piero Olliaro). What's been very interesting about these talks is the quality of the questions I've been getting about the project – a constant stream of insightful points, about both the chemistry and the way the project is run. For example, someone asked whether we have screened the enamide itself against the parasite (not as far as I know); the use of this compound would eliminate the problem of the stereocentre. My gut tells me that double bond would make the compound more toxic and more promiscuous. Anyone? My PhD buddy Matt Gaunt asked whether we could develop a method of simultaneously oxidising and reducing PZQ in a kind of dynamic kinetic resolution (something that would require a lot of R&D investment but which would be a beautiful approach). Jonathan Goodman asked whether, if lots of people did open science, there would be less input because people would be more diluted. This is a very interesting point, but I don't think so, and would take the large and vibrant open source software movement as the precedent. If there are any more questions, just post them…
 

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MatTodd's picture

Bill Jackson from Creative Chemistry alerted me to this nice paper detailing the synthesis of some relevant tartaric acid-based resolving agents. We have an undergrad in the lab in Sydney, Clara, who's doing some resolving agent synthesis at the moment with Michael, posting data here. I'll describe this new student-based project more shortly.