Developing medicines from nature’s bounty

There was a time when all our medical “cures” came directly from wild plants and animals. Today we generally synthesize our drugs, but 40 to 50 percent of them still have their origins in nature. Aspirin, for example, is a synthetic derivative of an active ingredient in the bark of the willow tree. (The ancient Greeks and Romans used ground-up willow bark to reduce pain.) Other natural sources of today’s drugs include Botulinus bacteria (Botox), soil bacteria (streptomycin), mould (penicillin), and opium poppies (morphine). Some 60 percent of our anti-cancer drugs and 75 percent of infection-fighting drugs have natural origins.

The quantities found in nature, however, are minuscule. So for us to benefit from them, they must be synthesized. This is where SFU’s Rob Britton, a “synthetic chemist,” comes in.

No, Britton himself isn’t synthetic. The word doesn’t mean artificial in this case. Instead, it describes the job of building (synthesizing) complex organic molecules from small chemical bits and pieces. Think Lego toys. “Synthetic chemistry is immensely challenging,” Britton says, “because 90 percent of the time your experiments fail.”

The hard part is figuring out how to duplicate artificially each natural drug – in 10 or fewer steps. “With each step, you need to figure out the precise conditions for a piece to attach correctly to other pieces.” If it takes more than 10 steps, the synthetic version will be nearly impossible to mass produce. And because each step takes the chemist into uncharted territory, it can take years to figure out a viable production method.

Tapping into nature’s medicine cabinet

Most natural drugs are found in plants and animals that spend their lives attached to something hard (such as fungi, corals, sponges, and sea squirts) or something rooted in the ground (trees, bushes, more fungi). They are most common in species that live in crowded conditions that must compete with other species for the available space. Unable to physically flee or defend themselves, they produce toxins that harm or irritate anything that attacks them. Divers in the tropics often experience this phenomenon first hand if they accidentally brush a bare arm or leg against a coral. The resulting burning sensation and red marks are caused by the sorts of toxins that are useful in fighting disease.

Different natural molecules fight disease in different ways. Taxol, for instance, which comes from the Pacific yew tree, interferes with the process of cell division, killing cancer cells while having minimal effect on normal cells.

For many years researchers have been grinding up plant and animal samples and testing the soupy brew for cancer- or disease-fighting characteristics. “Within an extract from a sponge or a tree,” notes Britton, “you’ll end up with thousands of chemical compounds.

One hundred different extracts can contain 100,000 different compounds, which represent a huge diversity of molecular structures. Now, if you screen those extracts for a particular disease-fighting activity, you might get one compound out of the 100,000 showing the activity you seek.”

In fact, there are specific tests for each disease-fighting mechanism. Say you’re looking for a new drug that will disrupt cell division (mitosis) and kill cancer cells. “There are ways to detect this activity,” says Britton. “You add your extract to a living culture of cancer cells, incubate the mixture, then perform an ‘enzyme-linked immunosorbant’ assay. Cells stuck in mitosis end up being labelled with a fluorescent tag, which makes them fluoresce. We can then use this activity to help track down and isolate the compound that halted mitosis. ”

Duplicating nature’s drugs in the lab

Rob Britton’s group is working on three intriguing compounds. One is latrunculin, which could help stop the spread of cancer cells. Found in Red Sea sponges, latrunculin disrupts the growth of the micro-filaments that cells need in order to move around.  

Another intriguing compound is eleutherobin, a substance isolated from certain corals. It kills cancer cells the same way Taxol does, but it may prove to be a better resource. “Taxol has some bad side effects and it can’t be made in the lab,” notes Britton. “Right now drug companies [have to] extract a precursor to Taxol from a bush that can be grown in bulk, then convert the precursor into Taxol. Eleutherobin could replace Taxol. Only tiny amounts are available, but I think we can develop an effective way to synthesize it.”

Finally there’s chimonanthine. Found in an evergreen shrub (Chimonanthus), it’s an old remedy for headaches, earaches, and other sources of pain. At one time people would boil the leaves and chew on them. Unfortunately its molecular structure is highly complex, and it takes 17 steps to synthesize. “We’ve developed on paper what we think is an efficient way to synthesize it in five or six steps,” says Britton.

For duplicating natural molecules in the lab, the Britton research group relies heavily on the chemistry department’s new high-field nuclear magnetic resonance (NMR) spectrometer, which is basically a medical MRI unit, but more powerful. With MRI, doctors view tissues and organs; with NMR, scientists observe organic molecules. Britton and his colleagues use the NMR spectrometer to determine the physical structure of natural products.

“Once we know the molecular structure, we look for cheap chemicals that can be hooked together to create that structure. Then it’s a matter of piecing the little bits together to make the molecule.” After each attempt to join pieces together, they use the NMR to see if they were successful. Finally NMR spectroscopy can show them how the newly synthesized molecule interacts with normal body proteins or enzymes. “We may even tweak the molecular structure to improve its activity.”

During the aq interview in his office, Britton pulled out a thick paperback that resembled one of those old Sears catalogues from the early 1900s. It was a Sigma-Aldrich catalogue, crammed with descriptions of thousands of chemical bits and pieces. “We search through this catalogue and order our chemical building blocks from it,” he says. “It’s like any other catalogue, except that it displays chemicals instead of clothes or toys or furniture.”

If it is true that Britton’s research involves months and years of failures, one might wonder how he survives the academic “publish-or-perish” culture – and win research grants.

“Universities and granting agencies understand that synthetic chemistry is slow to get results. They also know it’s one of the most important training grounds for future pharmaceutical chemists [who] need synthetic skills, knowledge of different

synthetic methods, and the ability to overcome obstacles.” Indeed, with our aging population, the increasing outbreaks of drug-resistant diseases, and the appearance of new disease organisms, synthetic chemists are becoming increasingly important.

All through the interview, Rob Britton was relaxed and smiling. Does he ever get mad? “I get frustrated, but not mad. I go home and within two minutes I’ve forgotten about everything. Having a cheerful and happy approach to life is essential in the synthetic chemistry business.”. aq

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