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Past Winner
2008 E.W.R. Steacie Memorial Fellowship

Dennis Hall

Chemistry

University of Alberta


Dennis Hall
Dennis Hall

Today's chemists can make virtually any molecule they choose. The real challenge, says organic chemist Dennis Hall, is figuring out which molecule will serve a useful, specific purpose, then finding a way to produce that compound efficiently.

Chemists can approach the problem of designing a useful molecule in two ways. In some cases, they know exactly what kind of structure will work, and set about making it. Other times, they may know only that the best candidate will come from a certain class of chemicals, in which case it is better to produce a large number of variations in the hope that one of them will do the trick.

Dr. Hall focuses his efforts on a family of compounds known as boronic acids and esters, as part of a diverse research program with potential applications ranging from medicine to industrial processes. “I was attracted by the fact that they are so versatile,” he says. “They're molecular jacks of all trades.” Working in a highly competitive field, he has discovered significant new uses for these compounds while also making major theoretical contributions. Receiving a 2008 NSERC E.W.R. Steacie Memorial Fellowship will help him continue and expand those efforts.

Boronic acids, composed of the semi-metallic element boron, were neglected for a long time because other compounds could perform many of the same functions. That began to change during the late 1970s, and has accelerated in the past decade. One of their advantages compared to other semi-metallic compounds lies in their relatively low toxicity. They are able to undergo a wide variety of reactions, and can form covalent bonds – bonds that involve sharing pairs of electrons – with a variety of oxygen- and nitrogen-containing organic compounds. Covalent bonds are normally quite strong, but in the case of boronic acids, they can be reversed by adding water, a unique characteristic that Dr. Hall has turned to his advantage.

One of his recent discoveries is that certain boronic acids are particularly good catalysts for making amides (important compounds whose functions include bonding peptides together, which in turn form proteins). Amides appear in more than a quarter of all pharmaceutical drugs, but traditional methods to manufacture them are complicated and generate a lot of waste, some of it toxic. Dr. Hall's method, in contrast, can be performed easily at room temperature and leaves only water as a by-product. It's such a simple process that he speculates it could even yield clues about the origins of life by showing how amino acids first assembled to become proteins in the presence of boric acid.

Dr. Hall's work on boronic acids helps further efforts to make chemistry more environmentally friendly by increasing the efficiency of chemical processes and producing less waste. “Sometimes it does chemistry that other elements do, but it is really worthwhile to develop the same reaction with boron because it is less toxic,” he says.

He makes extensive use of a powerful technique called combinatorial chemistry. “Combichem” uses tools and processes that make it possible to create and evaluate libraries (large collections) of related molecules, rather than designing them one by one through trial and error. The pharmaceutical industry makes extensive use of this approach in drug development.

Combinatorial chemistry has been a big help in recent work that uses boroxoles – a subclass of boronic acids – to solve a problem that has stumped scientists so far, namely developing molecules that can bind to the kind of complex sugars that form the outer coating of cells according to their specific “glyco-signature.”

“It's very hard to design synthetic receptors, or small molecules, that can bind to cell-surface sugars,” says Dr. Hall. “What we want to do is append these sugar-binding boroxoles to other molecules like peptides and make libraries of different ones, with different shapes and structures, and identify specific ones that could be selected for biologically important cell-surface carbohydrates.”

One of his first targets for these “synthetic antibodies” is a disaccharide called the T-antigen, which is one of the body's ways of flagging cancerous cells and is found in up to 90 per cent of human cancers. Developing a synthetic molecule that selectively binds to the T-antigen could prove to be a significant advance in the detection of cancer. Further down the road, it could even help with tumour-selective drug delivery.

Because boronic acids tend to be difficult to extract from water, Dr. Hall's lab had to develop new techniques in order to reliably synthesize whole libraries of the compounds. They use solid-phase synthesis – a technique that involves tiny resin beads that the desired compound will adhere to. All extra substances can then be easily removed by simple filtration, leaving only the target compound. Adjusting the makeup of the resin serves to customize the compound to which it will attach.

There is no shortage of problems that Dr. Hall and his lab could choose to tackle in the future. It seems fairly certain, however, that one of those highly versatile boronic acids will be part of the solution.