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Department of Chemistry

 

Courtesy Department of Chemistry Photography

Researchers here have successfully modified a well-known chemical reaction in such a way that it can produce drug molecules in a purer and more effective form.

The process they developed – which was published in Science in April – has the potential to reduce both the side-effects of drugs and the doses patients need to take. It may also cut the cost of producing them and the wastage involved in doing so, says principal investigator Dr Robert Phipps.

"I can't really believe the reaction works so well. It would be fantastic if our methodology were developed further and found some real use in the synthetic chemistry community."

Many drug molecules contain a building block called a heteroarene: a ring of carbon atoms that also contains a nitrogen atom. In drug discovery, an organic chemical reaction known as a Minisci reaction is often to used to attach specific molecules to this ring system in order to add therapeutic functions to the drug. Now Robert and two of his postgraduate students, Rupert Proctor and Holly Davis, have come up with a way to modify the Minisci reaction so that it can control which of the two enantiomers – the left-handed and right-handed forms – of a molecule it attaches to the ring. This is very important: while both enantiomers of a molecule have the same basic properties, where the right-handed form might produce the desired therapeutic effect, the left-handed form may at best be harmless and at worst cause unwanted or dangerous side effects.

When tested in the lab, and on two existing drugs, the reaction process the researchers developed selected one of the two possible forms of the molecule up to 49 times out of 50. "To the best of our knowledge," says Robert, "this is the first time a way has been found to make a Minisci reaction selective for one enantiomer over another." And he thinks it may open the door to many potential benefits.

"There are significant implications for pharmaceutical research in the synthesis of enantioenriched molecules – i.e. those that select one enantiomer over the other. It means you could be getting a purer form of the drug molecule because even if the unwanted enantiomer is harmless, having it in the drug molecule dilutes that molecule’s efficacy by 50 per cent, so you have to give twice as much of the drug to get the therapeutic effect."

Cutting down side-effects
And in addition, it may also cut down on side-effects, he says. "The often-quoted example of the effects different enantiomers have in the body is the thalidomide tragedy: one enantiomer of the drug molecule treated morning sickness in pregnant women but the other enantiomer caused birth defects. Being able to select much more accurately which enantiomer of a drug molecule you are making would be a significant help to pharmaceutical companies working to produce new drug treatments."

Developing the reaction
It was Rupert, a second-year PhD student co-sponsored by GlaxoSmithKline, who developed the reaction under Robert’s supervision. He says: "Having something behave for you this early in your PhD is quite rare: I can't really believe the reaction works so well. It would be fantastic if our methodology were developed further and found some real use in the synthetic chemistry community."

Holly, a final-year PhD student co-sponsored by Pfizer, worked on testing the reaction on a series of targets towards the end of her PhD studies. "I really enjoyed the chance to broaden my research experience by being involved in such an exciting project in this up-and-coming field," she says.

When their paper Catalytic Enantioselective Minisci-Type Addition to Heteroarenes was published in Science, it was picked up by a number of news outlets including Chemical & Engineering News and Phys.org. There is interest in the research because such a well-known chemical reaction has been used to modify a class of molecules frequently found in drug compounds. On top of that, the new process employs a method that is currently a very active field of research.

Photoredox catalysis is a method for converting light energy into chemical energy and it has led to a resurgence in free radical reactions (i.e. reactions that involve the movement of a single electron, rather than a pair of electrons). Minisci reactions are radical reactions, "and there has been a lot more attention paid to them to recently," says Robert, "because photoredox catalysis has made it easier to carry out single electron chemistry." This is thanks to the fact that LED strips that provide the light have become very cheaply and easily available, and scientists have developed catalysts that are able to harness their light energy and use it to modulate the movement of electrons in a reaction flask.

"But these single-electron reactions tend to be very fast and historically it has been quite challenging to control the chirality – i.e. whether you form a bond with the right-handed or left-handed enantiomer – in them because of their speed." Robert explains. "So actually controlling enantioselectivity in photo-redox radical reactions is a very hot topic as there are not many ways to do it. But we have developed a method that I think will gain a lot of attention."

Use in new drug development
It is a two-step process that employs two catalysts, one taking light from the LEDs and turning it into chemical energy to move the electrons, and the other controlling which form of the enantiomer bonds with the heteroarene. To showcase the way in which it works, the researchers tried it out on two drugs: clofibrate, formerly used as a treatment to lower cholesterol, and metyrapone, a drug used in diagnosing adrenal insufficiency and treating the pituitary disorder Cushing’s disease.

"In the first stage of our research, we tested the process on 15-20 targets that were simple molecules," Robert explains. "But then we tested it on these two pharmaceuticals to demonstrate that it would work on more elaborate compounds."

And now that it has done, they hope that others will be interested in trying it out. "We are hoping someone will take it on to the next stage and use the method on therapeutics that are under development," Robert says. "We are keen just to get the results out there for people to use."

  • The research was funded by a number of sources: The Royal Society, EPSRC, GlaxoSmithKline and Pfizer.