Harrison, Paul - McMaster University - Department of Chemistry & Chemical Biology

个人简介

B.A. (Oxford), Ph.D. (Alberta)

研究领域

Bio-organic chemistry is the exciting area where chemists and life scientists overlap to tackle biological problems by means of atomic understanding. Our research in this area focuses on natural products from secondary metabolism. Secondary metabolites include many compounds important to man, such as antibiotics, perfumes, flavouring agents, toxins and narcotics. We are interested in three main areas: Biosynthesis Biosynthetic research involves the study of how complex naturally occurring organic molecules are constructed in nature from simple precursors. Our current work in this area uses appropriate precursors which have been labelled with isotopes such as deuterium, tritium, carbon-13 and oxygen-18 to study how these molecules are assembled and modified in vivo to generate polyketides, such as the -lactone F-244 (1)1, and pramanicin (2)2-4. This research involves a mixture of organic synthesis to make the prerequisite labelled compounds, microbiology to grow antibiotic-producing micro-organisms, enzymology, chemical purification of the product, and extensive use of NMR to locate the label. The genes responsible for assembly of these complex structures are also being identified. Antibiotic Mechanisms of Action The -lactone 1 acts as an inhibitor of HMG-CoA synthase, an important enzyme in the biosynthesis of cholesterol, and thus has potential as an anti-hypercholesterolemic drug. We are therefore investigating how this inhibition takes place at the chemical level, using -lactones prepared by organic synthesis in our laboratory as well as by collaborator D. Romo (Texas A&M Univ, U.S.A.) and enzyme prepared in our laboratory using cloning techniques.5,6 We plan to use X-ray crystallography to determine the 3-dimensional structure of the enzyme. Molecular modelling will then be used to test hypotheses for the binding of 1 in the enzyme active site. This work involves synthesis, enzymology and some genetics and microbiology. Pramanicin2 is active against Cryptococcus neoformans, the causative agent of cryptococcal meningitis. In collaboration with D. Kwan, (Health Sciences, McMaster) we are studying the mechanism of action of this antibiotic. We have shown that pramanicin influences endothelial cells and the contraction of smooth muscle, a process which occurs in asthma7. Recent evidence suggests that 2 acts on the nitric oxide synthase pathway and impacts cellular calcium transport. Analogs of 2 are being prepared for Quantitative Structure Activity Relationships (QSAR) to determine which part(s) of the molecule are responsible for activity. This work involves chemical synthesis. Biomimetic Synthesis Living organisms effect a wide variety of chemical transformations in a remarkably efficient and selective manner: many reactions in research and industry utilize naturally occurring enzymes or micro-organisms. We are learning from nature how to achieve efficient and selective Claisen condensations, such as occur naturally in the formation of the compounds 1&2 (above), in a purely chemical fashion. Specifically, the research involves the intramolecular Claisen-like condensation of two acyl units which have been attached to a single glycoluril "template" molecule. We have demonstrated that the glycoluril template 3 can be sequentially acylated to give derivatives 4, which undergo intramolecular Claisen-like condensations to give 5.8 This system models some of the features of the enzymic process, and allows for iterative addition-condensation sequences to give long carbon chains.8,9 We have extended this work to develop a biomimetic synthesis of the fatty acid component of pramanicin (2).9 Other approaches allow control over the regiochemical outcome of the intramolecular Claisen condensation.9,10 Understanding of the mechanism of this reaction is being developed through X-ray crystal structures of these glycolurils.10-14 and kinetic analysis of the reaction.15 The project involves extensive preparative organic synthesis, as well as the use of NMR and other spectroscopic techniques for analysis of products.

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Saepudin, E., Harrison, P. H. M. "The Biosynthesis of Antibiotic F-244 in Fusarium sp. ATCC 20788: Origin of the Carbon, Hydrogen and Oxygen Atoms. "Can. J. Chem., 73, 1-5, 1995. Harrison, P. H. M., Hughes, D. W., Riddoch, R. W. "The Biosynthesis of Pramanicin: Origin of the Carbon Skeleton. "J. Chem. Soc., Chem. Commun., 273-274, 1998. Duspara, P. Hughes, D.W., Harrison, P.H.. "The Biosynthesis of pramanicin: intact incorporation of serine, and the absolute configuration of the antibiotic. J. Chem. Soc., Chem.Commmun., 2643-2644, 1998. Duspara. P. Jenkins, S.I. Hughes, D.W., Harrison, P.H.M. "The Biosynthesis of pramanicin in Stagonospora sp. ATCC 74235: a modified acyltetramic acid". J. Chem.Soc., Perkin Trans. 1, 4390-4402, 2000. Bell, K., Saepudin, E., Harrison, P. H. M. "Irreversible inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A synthase from yeast by F-244 and (RS)--butyrolactone. "Can. J. Chem., 74, 24-27, 1996. Romo, D., Harrison, P. H. M., Jenkins, S. I., Riddoch, R. W., Park, K., Yang, H. W., Zhoa, C., Wright, G. D. "Synthesis and Inhibitory Action on HMG-CoA Synthase of Racemic and Optically Active 2-Oxetanones. "Bioorg. Med. Chem., 6, 1255-1272, 1998. Kwan, C.Y., Harrison, P.H.M., Duspara, P.A., Daniel, E.E. "Vasorelaxant Effects of Pramanicin, an Anti-fungal Agent: Selective action on endothelial cells "Jpn. J. Pharmacol., 85, 234-240, 2000.Sun, S., Harrison, P. H. M., Edwards, L. Glycoluril as an Efficient Molecular Template for Intramolecular Claisen-type Condensations. "J. Chem. Soc., Perkin Trans. 1, 437-448, 1998. Cow, C. N, Valentini, D., Harrison, P. H. M. "Synthesis of the Fatty Acid of Pramanicin. "Can. J. Chem., 75, 884-889, 1997. Cow, C. N., Harrison, P. H. M. "A Facile Preparation of Thioglycolurils from Glycolurils, and Regioselectivity in Thioglycoluril Template-Directed Crossed-Claisen Condensations. "J. Org. Chem., 62, 8834-8840, 1997. Sun, S., Britten, J. F., Cow, C. N., Matta, C. F., Harrison, P. H. M. "The Crystal Structure of 3,4,7,8-tetramethylglycoluril. "Can. J. Chem., 76, 301-306, 1998. Cow, C. N., Britten, J. F., Harrison, P. H. M. "X-Ray Crystal Structure of 1,6-diacetyl-3,4,7,8-tetramethyl-2,5-dithioglycoluril, a Highly Twisted Acetamide. "J. Chem. Soc., Chem. Commun., 1147-1148, 1998. Matta, C., Cow, C., Sun, S., Britten, J.R., Harrison, P.H.M. "Twisted amides: The x-ray crystal structures and computational analysis of 1-acetyl-3,4,7,8-tetramethylglycoluril and 1,6-diacetyl-3,4,7,8-tetramethylglycoluril. "J. Mol. Struct., 523, 241-255, 2000. Duspara, P.A., Matta, C.F., Jenkins, S.I., Harrison, P.H.M. "Twisted Amides: Synthesis and Structure of 1,6-dipivaloyl-3,4,7,8-tetramethyl-2,5-dithioglycoluril. "Org. Lett., 3, 495-498, 2001 Rahimizadeh, M., Kam, K., Jenkins, S.I., McDonald, R.S., Harrison, P.H.M.. "Kinetics of glycoluril template-directed Claisen condensations and mechanistic implications. "(Manuscript in preparation)