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ScienceWise - Spring 2013

Inspired by nature

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Better pathways to new medical compounds

For thousands of years humans have known that certain plants hold medicinal properties and have gathered those plants to treat a variety of ailments. Many modern medicines, such as aspirin derived from the bark of willow trees, have natural origins too. If a plant is commonly available and the active molecule works well in its natural form, then there’s no problem. But what if we need to modify a natural product to increase its efficacy and reduce undesirable side effects, or what if a clinically important agent is only found in an endangered species? In situations like these synthetic chemists are frequently called upon to develop methods to access these important molecules in an economically and ecologically sustainable manner.

The kingianin natural products were recently isolated from the bark of the rare Medang tree found in Malaysia and Borneo, and have great promise as lead compounds in the development of novel cancer therapies. Frustratingly, the bark of an entire tree only produces a vanishingly small quantity of these complex and biologically active compounds. This has hindered further medicinal studies, due to a lack of supply. 

Driven by a demand for a more sustainable route to these kingianin molecules, a team of chemists from the Australian National University elected to confront this challenge head-on, by investigating whether the kingianins could be prepared in the laboratory from scratch. 

“Just because something is natural doesn’t automatically make it safe, or a good medicine” Professor Mick Sherburn explains, “More often than not, molecules in their natural form have undesirable or even fatal side effects, so very few of them go to market unchanged. But what these natural products often do, is provide us with a raw material which we can modify into something really useful through synthetic manipulations in the laboratory.”

A group of researchers, led by Professor Mick Sherburn and Dr Andrew Lawrence, have recently developed a novel technique for the synthetic production of the kingianins, which has pushed at the boundaries of what was traditionally thought possible.

Synthetic chemists usually construct molecules one new bond at a time: reagents are introduced to a reaction vessel and specific conditions are applied to form just one new chemical bond. What the ANU group has developed is what’s known as a domino reaction, wherein lots of bonds are all formed in a single reaction – this is far more efficient, but also far more challenging to successfully execute.

“With a domino reaction, everything is designed to automatically happen selectively in the right sequence without any additional changes needed. The molecule essentially assembles itself.” Dr Andrew Lawrence says, “The really tricky bit is creating the right precursor molecule for the domino reaction.”

To achieve this the researchers produced a molecule that contained a long straight chain of eight carbon atoms. They then used a process to add many hydrogen atoms to the chain – something that has not previously been done on such a long carbon chain.

“Nature is a master chemist, so it’s a great place to seek inspiration.” Dr Lawrence adds,  “What we have done is combine state-of-the-art synthetic technology, which is available to us in the laboratory, with a synthetic strategy that mimics the processes actually used by nature to assemble these kingianin molecules in the tree. This so-called ‘biomimetic’ approach has resulted in a uniquely efficient synthesis.”

The researchers discovered that the tree utilized free radicals to make the kingianin molecules. “Free radicals are well known to break down biological molecules,” Professor Sherburn says. “Our work shows that nature has actually harnessed free radicals to create rather than destroy.”

But why is it that so many useful medical compounds are found in nature in the first place?

“Nature doesn’t create these molecules for it’s own amusement, if it goes to the considerable trouble of doing so, there must be a good biological reason.” Dr Lawrence says.

Samuel Drew, the PhD student who actually conducted the experiments in the lab, says “Our research isn’t directly involved in medical applications, what we’re really interested in is developing the science and art of synthetic chemistry. Our results show that by working smarter, chemical synthesis can be made more efficient, take less time and cost less money. We can also reduce energy consumption and waste production. So if the kingianins turn out to be the next hot thing in medicine, then our research will mean we don’t need to endanger the tree or destroy the environment to harness the biological activity of these intriguing molecules.”

This research was funded by the Australian Government through the Australian Research Council. It is published in the leading international chemistry journal, Angewandte Chemie.

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