Recipe for Success
Nick Ray

Recipe for Success

A team of young chemists from Charles River Early Discovery claims the top prize in the Royal Society of Chemistry's Retrosynthesis competition

As chemists at Charles River Laboratories, we are often asked what the difference is between medicinal chemistry and synthetic chemistry.

Medicinal chemistry is the practice of using data obtained from in vitro and biological assays, pharmacokinetic (PK) and pharmacodynamic (PD) in vivo assays as well as metabolism, safety and pharmaceutics assays to design a drug molecule that will be safe and efficacious, via a pre-defined route of administration, in humans. Synthetic chemistry is the discipline of working out, based on a large knowledgebase of technical expertise, how to actually build the molecules that our medicinal chemistry insights have led us to.

A more simplistic answer could thus be that medicinal chemistry encompasses "What should we make" and synthetic chemistry "How shall I make it." Medicinal chemistry is also a skill that is largely acquired doing drug discovery 'for real' at CROs like CRL, biotechs or pharmaceutical companies, whereas synthetic chemistry is first encountered during the undergraduate chemistry degree at University and then significantly enhanced during a PhD and possibly two years of post-doctoral study. On leaving University to join an organisation such as Charles River Discovery the chemists' focus starts to turn towards acquiring medicinal chemistry skills; however the need for strong synthetic skills remains absolute.

It is for this reason that the Royal Society of Chemistry (RSC) in the UK initiated a biannual synthetic chemistry competition to showcase the strength of synthetic chemistry in UK industry and academia. First held in 2013 the competition is limited to 'young' chemists (under age 35). Academic groups, biotechs, pharma and CROs are invited to enter teams (some organisations enter more than one!) that compete head-to-head to see who has the top synthetic chemistry skills. In 2013, a team from Oxford University won, with the CRO Sygnature Discovery placing second. Charles River did not possess a chemistry group back then, but the CRO Argenta where I work—and which Charles River acquired last year along with Argenta's sister site BioFocus—fielded a team. This year we decided to enter a single team consisting of chemists from both Argenta and BioFocus, rather than two separate teams. Why? Because since the acquisition we've looked for ways to bring the staff of the two companies (former competitors in the CRO world) together.

Hence it was in December of 2013 that Pascal Savy, a veteran of the last competition but now too old(!) to compete, pulled together our 'One ED' team of Coura Diene, William Esmieu, Stephen Penrose (BioFocus) and Andrew Roupany, Jonathan Killen, Joe Marshall, Sam Mann and Paul Winship (Argenta).

Round One—Surviving the Qualifier

Molecular diagram for Myrothecol AThe competition is run in two rounds, with 10 teams moving from the qualifying round to reach the final at the RSC headquarters in London. The challenge at both stages is the same: the judging panel provides each team with the same molecule and the team needs to devise a possible route to make it. The route is on paper only, no practical chemistry is undertaken. The final compound is broken down step-by-step (the "retrosynthesis") into chemically sensible smaller parts until one arrives at commercially available starting materials. The chemists then use their knowledge of chemical reactions to identify means of assembling the parts back together.

In a lot of ways chemistry is like baking a very elaborate surprise cake, except in our case we were given the picture of the cake and asked to break it down into its component parts—decoration, frosting, flavorings (the retrosynthesis)—and then reassemble it to look exactly the same as the picture: amount of ingredients, temperature, cooking time and so on (the forward synthesis).

Our first-round target was the natural product Myrothecol A (quinone sesquiterpene isolated from cultures of the fungus Myrothecium sp. SC0265 if you are interested in learning more)! This was not going to be straightforward considering the complexity of the target and the fact we had only communicated as a team by email. We compiled our ideas and had our first meeting in the boardroom at CRL Harlow. After some excellent and thought-provoking discussion we had our route to Myrothecol A, made some new cross-site connections and remembered the essence of being a synthetic chemist. We submitted our ideas and waited (watching the oven closely) and were delighted to find out that our design was one of 10 chosen from a very strong field of 50 entrants!

Round Two—Off to the Finals

Alistonitrine A, extracted from Alstonia scolaris, 15kg of leaves gives 5mg of Alistonitrine AA few weeks before the final round we were given an even more complex molecule, Alistonitrine A, containing the unprecedented caged skeleton with a unique 6,5,6,5,5,6 ring system. The plant Alstonia scholaris has long been used in traditional Asian medicine for the treatment of a number of conditions including respiratory disease, malaria and dysentery. Several monoterpene indole alkaloids have been extracted from the leaves and bark; 15kg of air-dried leaves yielded 5mg of Alistonitrine A, hence finding synthetic routes in to such compounds will facilitate further study of this interesting compound.

Once again the team met to pull the molecule apart and find ways of putting it back together again, many times finding ourselves at a dead end and having to start again. We also had the guidance of the judges to consider. Since we wouldn't be able to try out our syntheses for real to know which worked best we would be judged on a combination of ingenuity, tractability and the quality of the presentation. Our route therefore needed to strike a balance of inventive chemistry with something that had a chance of actually working!

The day of the competition we were excited to see what the other finalists had produced, secretly hoping that none rivaled our efforts. Each team had a 20-minute presentation slot followed by questions from the floor, some from the judges and some from the other teams looking to sink the opposition! The quality of the presentations was uniformly high, with a surprising diversity of approaches. At 3:00 pm we unveiled our creation to the judging panel and our competitors and after months of preparation, an expertly delivered presentation, and some tough questioning we awaited the final results.

Charles River placed first followed by Oxford University and Manchester University. We were delighted, of course, but for me the real rewards were twofold: the opportunity to bring the Argenta and BioFocus chemistry teams closer together and the knowledge that synthetic chemistry is alive and well in the UK both in academia and industry—and especially Charles River, where we do it particularly well.

Charles River Team

An update

For an inside look at what it felt like to compete, check out CR scientist Stephen Penrose's April 27 post that appeared on Chemistry World’s Natural Products Blog.