Chemical Education Today
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Research Advances by Angela G. King
Revealing Secrets of “African Sleeping Sickness” Scientists in the United Kingdom and Russia report identification of a long-sought chink in the armor of the parasite that causes African sleeping sickness, a disease that kills at least 50,000 people each year. Michael Ferguson and colleagues cite an “urgent” need for new treatments for the disease, which is spread by the tsetse fly and also affects cattle—a precious possession that represents a four-footed bank account to impoverished people in subSaharan Africa. Current treatments for African sleeping sickness, Ferguson says, are not only difficult to administer but also expensive and toxic. Their research identified the first compound to impede a key step in an essential biochemical pathway in the sleeping sickness parasite Trypanosoma brucei. Blocking this pathway disrupts the production of a key glycolipid, glycosylphosphatidylinositol (GPI), which anchors protective proteins to the surface of the parasite. Disruption of GPI biosynthesis is validated as a drug target, so Ferguson’s research team looked at how enzymes involved in GPI biosynthesis recognize and process analogs of the natural substrate dimannosyl-glucosaminylphosphatidylinositol (Man2GlcN–PI) that were synthesized with modifications on the mannose unit. The researchers analyzed which analogs were substrates for enzymes in the biosynthetic pathway to determine which features of Man2GlcN–PI are necessary for recognition by different enzymes. Their results indicate that the natural diacylglycerol lipid moiety is not necessary for processing along the pathway (Figure 1). One specific enzyme, a mannosyltransferase referred to as MTIII, does not recognize the amine of the glucosamine residue, but does require hydroxyl groups at the 2and 3-positions of the reducing terminal mannose. The enzyme inositol acyltransferase needs a free amine on the glucosamine residue and a hydroxyl group at the 4-position of the first mannose for recognition. The analysis also revealed notable differences between pathways of parasitic and human cells. Mammalian MTIII has a more complex natural substrate than the trypanosomal MTIII
studied in this work. A comparison of previous work to these new results suggests that mammalian MTIII and trypanosomal MTIII may have distinct requirements for recognition of substrates, which leaves the door open for species-specific inhibition and possible therapeutic targets. More Information 1 Urbaniak, Michael D.; Yashunsky, Dmitry V.; Crossman, Arthur; Nikolaev, Andrei V.; Ferguson, Michael A. J. Probing Enzymes Late in the Trypanosomal Glycosylphosphatidylinositol Biosynthetic Pathway with Synthetic Glycosylphosphatidylinositol Analogues. ACS Chemical Biology 2008, 3, 625–634. 2. For more insight into new drug discovery initiatives at the University of Dundee, see http://www.drugdiscovery.dundee.ac.uk/ (accessed Jan 2009). 3. http://www.lifesci.dundee.ac.uk/people/mike_ferguson/research/ (accessed Jan 2009) provides much information on research in this and related projects in Dundee’s laboratories. 4. This Journal has published a description of the use of molecular modeling in medicinal chemistry. See J. Chem. Educ. 2005, 82, 588.
New Synthesis Approach, More Durable and Elastic Material? In the not-so-distant future, plastics could be more durable and rubbers could be more … well … rubbery thanks to a novel approach to polymer synthesis discovered by Texas Tech University organic chemists. The scientists demonstrated what principal investigator Michael Mayer refers to as an “elementary” process for ultimately creating a slip-linked pulley system of molecules that could be used to fabricate tougher and more elastic synthetic materials. “It is a fundamentally new approach to the synthesis of this class of polymeric materials”, said Mayer, an assistant professor of organic chemistry in the Department of Chemistry and Biochemistry. Mayer’s findings provide a novel way to form unusually complex polymers. Current methods for creating related poly-
Figure 1. Summar y of the features of Man 2 GlcN–PI recognized by MTIII and the inositol acyl transferase. Reprinted with permission from ACS Chemical Biology 2008, 3, 625–634. Copyright 2008 American Chemical Society.
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Figure 2. Scientists have elucidated a new method of creating a slip-linked pulley system for crosslinking molecules that could lead to more elastic materials. Reprinted with permission from J. Am. Chem. Soc. 2008, 130, 15246–15247. Copyright 2008 American Chemical Society.
mer networks rely on chemical reactions to cross-link the large molecules. However, when the resulting materials come under physical stress, Mayer said, the cross-links, which are often the weakest links, can break resulting in failure of the material. Mayer and his team, led by senior graduate student Songsu Kang, tried a different approach, beginning with molecules in the form of two interlocked rings—much like the rings used by magicians in the so-called “magic ring” trick. Starting with olefinic [2]catenanes, the chemists envisioned use of ringopening olefin metathesis polymerizations (ROMPs) to produce polypseudorotaxanes. The resulting materials would have rings that can literally slide along the polymer chains, providing mobile anchor points for cross-linking that may be more “forgiving” when the structures are mechanically strained (Figure 2). The research team began by exploring a model ROMP on an uncatenated olefinic macrocycle (1) (Figure 3). Stirring
a solution of 1 with an initiator (namely Grubbs’ secondgeneration catalyst) for 4 h yielded a viscous solution. After the reaction was quenched with ethyl vinyl ether and the solvent was removed, the solid residue was determined to be compound 2 through 1H and 13C NMR spectroscopy and size exclusion chromatography, and the ratio of 1:2 was 7:93 in the product, with 2 having an average molecular weight of 116,000 amu. Based on these positive results, Mayer’s team moved on to the more complicated Sauvage-type [2]catenane monomer 3. The result was a reasonably high molecular weight polymer, i.e., the main-chain polypseudorotaxane (4). Mayer said this proofof-concept research could someday be used to create related pliable networks of polymers, and said this design enables access
Figure 3. Ring-opening olefin metathesis polymerization yielded model polymer 2 with an average molecular weight of 116,000 amu. ROMP-generated polypseudorotaxane 4 is proof-of-concept that could lead scientists to a new class of materials. Structure by M. Mayer.
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to polymer samples that embody some theoretical models used by polymer physicists. “Specifically, one useful theoretical model depicts polymer entanglements as if separate polymer strands are cross-linked via macrocycles (so-called slip-links),” he said. “Now, using this synthetic approach, we have a well-defined method to prepare rubbery materials that actually fit these descriptions.” More Information 1. Kang, Songsu; Berkshire, Brandon M.; Xue, Zheng; Gupta, Manav; Layode, Christianah; May, Preston A.; Mayer, Michael F. Polypseudorotaxanes via Ring-Opening Metathesis Polymerizations of [2]Catenanes. J. Am. Chem. Soc. 2008, 130, 15246–15247. 2. http://www.depts.ttu.edu/chemistry/Faculty/mayer/ (accessed Jan 2009) provides more information on research in this and related projects in Mayer’s laboratories. 3. This Journal has published many articles on the coverage of olefin metathesis in undergraduate education. See J. Chem. Educ. 2007,
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84, 1995; 2007, 84, 1998; 2006, 83, 192; 2006, 83, 283; and 1996, 73, 155. 4. The theoretical physics polymer entanglement model is described in Ball, R. C.; Doi, M.; Edwards, S. F.; Warner, M. Polymer 1981, 22, 1010–1018. 5. Mayer is pioneering the use of YouTube in advancing organic chemistry instruction. See http://www.youtube.com/profile?user=mfm ayer&view=videos (accessed Jan 2009).
Supporting JCE Online Material
http://www.jce.divched.org/Journal/Issues/2009/Apr/abs414.html Abstract and keywords Full text (PDF) with links to cited URLs and JCE articles
Angela G. King is Senior Lecturer in Chemistry at Wake Forest University, P.O. Box 7486, Winston-Salem, NC 27109;
[email protected].
Journal of Chemical Education • Vol. 86 No. 4 April 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
