Faculty & Staff Directory

Professor Timothy J. Hagen

Timothy J. Hagen

Assistant Professor
Office:  Faraday Hall 350
Phone:  (815) 753-1463

Educational Background

Postdoctoral Research Fellow, CNS & Drug Design, Searle, 1988-1989

Ph.D., University of Wisconsin-Milwaukee, 1988

B.S., Illinois State University, 1982

Curriculum Vitae

Research Interests

Organic Synthesis; natural product synthesis; medicinal chemistry; small molecule protein interactions; drug design.

Hagen Group Homepage

Representative Publications

  1. Travis Helgren, Timothy J. Hagen “Advances in Bacterial Methionine Aminopeptidase Inhibition” Current Topics in Medicinal Chemistry, 2015, in press.
  2. Helgren, T. R.; Sciotti, R. J.; Lee, P.; Duffy, S.; Avery, V. M.; Igbinoba, O.; Akoto, M.; Hagen, T. J., “The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.Bioorg. Med. Chem. Lett. 2015, 25 , 327-332.
  3. Helgren, T. R. and Hagen T.J.  Phthalazines Science of Synthesis, Knowledge Updates 2015, in press. 
  4. Hagen, T. J.; Mo, X.; Burgin, A. B.; Fox, D.; Zhang, Z.; Gurney, M. E., Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Bioorg. Med. Chem. Lett. 2014, 24 , 4031-4034.
  5. Zhang, Z.; Jakkaraju, S.; Blain, J.; Gogol, K.; Zhao, L.; Hartley, R. C.; Karlsson, C. A.; Staker, B. L.; Edwards, T. E.; Stewart, L. J.; Myler, P. J.; Clare, M.; Begley, D. W.; Horn, J. R.; Hagen, T. J., “Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei.Bioorg. Med. Chem. Lett. 2013, 23 , 6860-6863.
  6. Wangtrakuldee, P.; Byrd, M. S.; Campos, C. G.; Henderson, M. W.; Zhang, Z.; Clare, M.; Masoudi, A.; Myler, P. J.; Horn, J. R.; Cotter, P. A.; Hagen, T. J., “Discovery of inhibitors of Burkholderia pseudomallei methionine aminopeptidase with antibacterial activity.ACS Med. Chem. Lett. 2013, 4 , 699-703.
  1. Dalby, A.; Mo, X.; Stoa, R.; Wroblewski, N.; Zhang, Z.; Hagen, T. J., “A concise synthesis of biaryl PDE4D allosteric modulators.” Tetrahedron Lett. 2013, 54 , 2737-2739.
  2. Hagen, T. J., 1,2-diselenins (update 2011). Sci. Synth., Knowl. Updates 2011,  , 93-97.
  3. Hagen, T. J., 1,4-diselenins (update 2011). Sci. Synth., Knowl. Updates 2011,  , 99-102
  4. 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., Optimization of a Pd-catalyzed intramolecular α-arylation synthesis of tricyclo-[,7]-trideca-2,4,6-trien-13-ones.Tetrahedron Lett. 2010, 51 , 4441-4444.
  5. Burgin, A. B.; Magnusson, O. T.; Singh, J.; Witte, P.; Staker, B. L.; Bjornsson, J. M.; Thorsteinsdottir, M.; Hrafnsdottir, S.; Hagen, T.; Kiselyov, A. S.; Stewart, L. J.; Gurney, M. E., “Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.Nature Biotechnology 2010, 28 , 63-70.

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. Trimeric crystal structure of BpIspF bound to FOL717 (light/dark green; PDB code 3IKF) with zinc atom (gray) aligned with two monomeric copies PfIspF bound to CDP (pink/magenta; PDB code 4C81) with catalytic zinc atom (yellow).

Certain enzymes are essential to bacterial and parasitic organisms such a R. prowazekii and P. falciparum and our approach is to use synthetic organic chemistry, medicinal chemistry and structural biology to design small molecule inhibitors of these enzymes. Methionine Aminopeptidase (MetAP) is a metalloprotease enzyme that removes the N-terminal methionine from nascent proteins and it is essential to humans and infectious disease causing organisms. The human forms of MetAP1 and MetAP2 enzymes have been well studied however, the MetAP1 form of R. prowezkii and P. falciparum form of MetAP2 have not. We are designing and synthesizing new molecules that will have potency and selectivity for the R. prowazekii MetAP1 and P. falciparum MetAP2. These compounds will be useful for treating typhus, malaria and other infectious disease.


Figure 2. R. prowazekii methionine aminopeptidase 1 in complex with methionine (green). (PDB 3MX6)

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.