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NIU Department of
Chemistry & Biochemistry
Where the study of matter...matters!
Professor Timothy J. Hagen
Assistant Professor
Office: Faraday Hall 350
Phone: (815) 753-1463
thagen@niu.edu
Educational Background
Postdoctoral Research Fellow, CNS & Drug Design, Searle, 1988-1989
Ph.D., University of Wisconsin-Milwaukee, 1988
B.S., Illinois State University, 1982
Research Interests
Organic Synthesis; natural product synthesis; medicinal chemistry; small molecule protein interactions; drug design.
Representative Publications
Optimization of a Pd-catalyzed intramolecular α-arylation synthesis of tricyclo-[7.3.1.02,7]-trideca-2,4,6-trien-13-ones. Powell, N.A.; Hagen, T.J.; Ciske, F.L.; Cai, C.; Duran, J.E.; Holsworth, D.D.; Leonard, D.; Kennedy, R.M.; Edmunds, J.J. (2010) Tet. Lett., 51: 4441-4444.
Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Burgin, A.B.; Magnusson, O.T.; Singh, J.; Witte, P.; Staker, B.L.; Bjornsson, J.M.; Thorsteinsdottir, M.; Hrafnsdottir, S.; Hagen, T.J.; Kiselyov, A.S.; et al (2010) Nature Biotechnology, 28(1), 63-70.
Zaitsev elimination. Hagen, T.J.; Ed. Li, Jie Jack; Corey, E.J. (2007) Name Reactions for Functional Group Transformations, 414-421.
Prilezhaev reaction. Hagen, T.J.; Ed. Li, Jie Jack; Corey, E.J. (2007) Name Reactions for Functional Group Transformations, 274-281.
5-Fluorinated L-Lysine Analogues as Selective Induced Nitric Oxide Synthase Inhibitors. Hallinan, E. A.; Hagen, T.J.; Bergmanis, A.; Moore, W.M.; Jerome, G.M.; Spangler, D.P.; Stevens, A.M.; Shieh, Huey S.; Manning, P.T.; Pitzele, B.S. (2004) J. Med. Chem., 47(4), 900-906.
3-Hydroxy-4-methyl-5-pentyl-2-iminopyrrolidine: a potent and highly selective inducible nitric oxide synthase inhibitor Tsymbalov S.; Hagen T.J.; Moore W.M; Jerome G.M; Connor J.R; Manning P.T; Pitzele B.S; Hallinan E.A. (2002)Bioorganic & Medicinal Chemistry Letters, 12(22), 3337-9
Syntheses of new conformationally constrained S-[2-[(1-iminoethyl)amino]ethyl]homocysteine derivatives as potential nitric oxide synthase inhibitors Wang, L.J.; Grapperhaus, M.L.; Pitzele, B.S.; Hagen, T.J.; et al (2002)Heteroatom Chemistry, 13(1), 77-83
Design and Synthesis of Molecules with Biological Significance
Research interests in our laboratory are at the interface of chemistry and biology. The focus is on structure-based design and synthesis of small molecules that can modulate essential pathways of infectious disease organisms with an emphasis on small molecule-protein interactions and target specificity. Our laboratory utilizes fragment-based screening, de novo design, the design and synthesis of versatile fragment building blocks from natural products, and construction of fragment libraries to explore enzyme selectivity.
Specific areas of interest include: (1) Fragment-based design of novel small-molecules to selectively disrupt key enzymatic interactions in the non-mevalonate isoprenoid biosynthetic pathway; (2) Design of novel small-molecules to selectively inhibit the P. falciparum and bacterial forms of enzymes such as MetAP2; (3) Natural product synthesis with investigation of their biological activities. Our group uses a multidisciplinary approach toward achieving these research goals including synthetic organic chemistry, computer modeling, protein crystallography, molecular and cell biology.
Fragment based drug discovery is a rapidly growing technique in medicinal chemistry, that utilizes protein crystallography to discover unique fragments that bind to protein targets of biological interest. These low molecular weight fragments can then be optimized using medicinal chemistry techniques to obtain new compounds with low nM potencies. This can be achieved with a limited number of compounds, especially if good structural data is present. These techniques are being applied to enzymes in the non-mevalonate isoprenoid biosynthetic pathway. We have established collaborations with research groups that have excellent structural capabilities and experience.
Figure 1. Crystal structure of IspF from Burkholderia pseudomallei
in complex with D161829. (PDB ID 3KE1)
Certain enzymes are essential to parasitic organisms such a P. falciparum and our approach is to use synthetic organic chemistry, medicinal chemistry and structural biology to design small molecule inhibitors of these enzymes. The human form of MetAP2 has been well studied however the P. falciparum form of MetAP2 has not. We are designing and synthesizing new molecules that will have potency and selectivity for the P. falciparum MetAP2 and these compounds will be useful for treating malaria and other infectious disease.
Figure 2. Human methionine aminopeptidase in complex with
bengamide inhibitor, LAF153 (cyan). (PDB 1QZY)
We are interested in synthetic methodology to natural products, such as the bengamides, that demonstrate interesting biological activity. The bengamides show anticancer, antibiotic and antihelmintic properties. Divergent synthetic routes to bengamide analogs will allow for rapid synthesis of novel analogs that may lead to improved treatments for infectious disease including malaria.
Figure 3. Structure of bengamide E.