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Research Profiles

Paul Harrison

Organic chemists have learned to alter and manipulate the arrangement of bonds between carbon and other atoms in molecules, creating new compounds with novel properties. These substances may have practical applications, such as new antibiotics, or may be of intellectual interest, perhaps offering new insights into the nature of matter. However, nature may be the ultimate organic chemist: in natural products, she produces organic structures of amazing complexity with an apparent ease of which the synthetic organic chemist might only dream. These natural products, also known as secondary metabolites, are produced by one or only a few species, and include compounds such as penicillin and other important common drugs. Their complex chemical structures are generated by a long sequence of biochemical reactions. Determining the events in this cascade is the realm of the biosynthetic chemist.

We are studying the pathways for formation of two metabolites, F-244 and pramanicin. F-244 inhibits a key enzyme in cholesterol biosynthesis, and is thus of interest as a potential cholesterol-lowering, and antifungal drug, while pramanicin is active against Cryptococcus, the causative agent of meningitis in immune-compromised individuals, such as those with AIDS. We have shown that both of these molecules are derived from the polyketide pathway, in which simple acetate units are stitched together repetitively to generate long chains of carbon atoms. Our long-term goal is to isolate the genes and proteins that catalyze antibiotic biosynthesis. By mixing these genes with those which encode other antibiotics, hybrid compounds of mixed structure, which may have novel anti-microbial properties, might be produced.

Glycoluril template 3 is sequentially acylated to give 4 which undergoes intramolecular Claisen-like condensations to give 5

We are also studying the ways in which antibiotics such as F-244 and pramanicin exert their anti-microbial effects. Molecular details of the chemical reaction occurring between F-244 and the cholesterogenic enzyme that it inhibits are being probed. In collaboration with D. Kwan (Biomedical Sciences, McMaster), we have shown that pramanicin affects calcium transport in cells, suggesting that pramanicin may have anti-cancer activity.

Our third avenue of research involves mimicking some of the features present in the remarkable enzymes that catalyze formation of secondary metabolites. We have developed a small organic molecule that mimics several aspects of the giant enzymes that manufacture polyketides. Our "working molecular model" allows for the repetitive stitching together of acetate units to give polyketides in a sequence of reactions that is analogous to that occurring in nature. We are also continuing to explore the fundamental chemistry of this system, which reveals novel nuances at every turn. For example, one molecule that we have recently prepared has an amide bond that is highly twisted, whereas amide structures are normally flat. Such twisted amides are of interest as models for transition states of protein hydrolysis, where it has been proposed that the enzyme enforces a twist upon the scissile peptide bond. The dream is to extend this model system to the preparation of novel antibiotics, and perhaps antibiotic "libraries" through the use of the important technique of combinatorial synthesis.

Alex Bain

Molecules are dynamic things. We tend to draw them as static structures, but there is always motion: vibration, internal rotation, weak bonds that break and re-form. When a molecular fragment moves, the nuclei move to a new magnetic environment. This means that Nuclear Magnetic Resonance (NMR) is particularly well-suited to study many of these motions: the effects on the NMR spectrum can be dramatic (see right). The classic example is dimethylformamide. At room temperature, the two methyl groups have two separate signals (bottom trace of the simulated spectra), since the rotation around the C-N bond is restricted by the partial double-bond character. However, as the rotation speeds up (higher T -upper traces), the signals broaden, coalesce and finally sharpen to a single, average line. By understanding these effects on the NMR lineshape, we can measure rates of these molecular motions quite accurately.

Dynamic NMR spectra. Successive traces (moving upward) show the effects of increasing temperature on a pair of lines related by chemical exchange. First the lines coalesce, then the one line sharpens about an average resonance frequency.

This study also provides a nice interplay between experiment and theory. Theoretically, it is easy to describe these lines in terms of a generalized "Golden Rule", with a transition probability which is a complex number. Experimentally, we have been able to sort out the dynamics of a molecule which has five different observable conformations. With our current set of powerful tools, we are starting to look at the important dynamic processes of peptides. These are usually very flexible by themselves in solution, but adopt very specific conformations in their biological environments. NMR provides a unique method for studying these conformations.

Many other systems are also dynamic. In collaboration with Randy Dumont, we have started to look at motions in solids. Even though the crystal lattice is maintained, molecules can still flex and rotate. Again, NMR gives us the most detailed picture of these motions. In fact, because of the sensitivity of NMR to orientation of molecules in solids, there is the possibility of observing molecular reorientation within a solid lattice in addition to transitions between conformations. This whole field of study is sometimes called "dynamic NMR", an appropriate name for all sorts of reasons.

Related Links: A.D. Bain Research Group P.H.M. Harrison Research Group

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