Over the years, several antiangiogenic compounds have been reported. Fumagillin, 1, is a natural product with antibiotic properties. This lead structure has served as template for the design of analogs.
The Bowen Research Group
J. Phillip Bowen
B.S. Chemistry, Piedmont College (1979)
Ph.D. Organic Chemistry, Emory University (1984)
The use of pharmaceutical agents, drugs, is one of the most effective treatments in modern medicine. Relying on drug therapies is an inexpensive and effective approach to combat various disease states, alleviate medical conditions, and function as useful preventive agents. Understanding how drugs interact with the human body and exploiting this information for the design of new medicines are major goals of the new Center for Drug Design. The Center for Drug Design was approved in 2004 by the administration and the Board of Trustees of the University of North Carolina at Greensboro. The Center members are focused on the development and use of computational chemistry and computer-assisted drug design methods, CADD, for understanding molecular structures, drug-receptor interactions, and drug design.
Dr. Bowen’s research interests span the fields of organic, medicinal, and theoretical chemistry. Specifically, the Bowen research group is using CADD methods for the design of novel antiangiogenic agents for the treatment of cancer and related diseases. Cancer is a broadly defined term used to describe not just one disease but many, each of which are characterized by abnormal cell proliferation. The underlying causes that bring about this abnormal cellular behavior are specific to each type of cancer. The success of tumor-targeted therapy has been limited by this diversity and other factors. Since all cancer cells require a suitable supply of blood, tumor vasculature is an interesting therapeutic intervention.
The basic idea behind the approach of antiangiogenisis treatment is to interrupt the new blood supply for tumors. The concept is based on suggestions first made by Judah Folkman. For continued growth, development, and functioning, tumor masses require a constant supply of oxygen and nutrients as well as efficient mechanisms for waste removal. Without this new blood supply, tumors will not grow beyond the size of approximately 2 mm and remain in a dormant stage. The process of blood vessel growth from preexisting vasculature, stimulated by biochemical signals, is termed angiogenesis. The goal of antiangiogenic therapy is to interfere with the mechanism of positive regulators of angiogensesis. In the Bowen group, a series of inhibitors have been developed based on the naturally occurring compounds fumagillin, 1, curcumin, 2, and solenopsin A, 3.
Over the years, several antiangiogenic compounds have been reported. Fumagillin, 1, is a natural product with antibiotic properties. This lead structure has served as template for the design of analogs.
Curcumin, 2, is a natural product isolated from the spice tumeric. The compound gives curry its characteristic yellow color. Curcumin exhibits a wide range of pharmacological properties ranging from anti-tumor, anti-hyperglycemic, to anti-tuberculosis activities.
The following graph displays some of the aromatic enone and aromatic dienone curcumin analogs that have been prepared based on a proposed pharmacophore model, as well as the angiogenic inhibition using the SVR assay carried out in the laboratories of our collaborator, Dr. Jack Arbiser, Emory University School of Medicine. One of the attractive features of curcumin analogs is the ease of preparation. These compounds may be readily prepared using Claisen-Schmit condensation conditions with various aromatic ketones and aromatic aldehydes.
Figure 1. Representative examples of aromatic enone and aromatic dienone curcumin analogs and their antiangiogenic activity based on the Arbiser SVR assay at various concentrations of 1, 3, and 6 g/ml.
Another extremely attractive lead compound discovered in the collaboration between the Bowen and Aribser groups is solenopsin A, 3.
Solenopsin A, 3, is the major alkaloid constituent of the fire ant venom. The antiangiogenic profile was discovered through our collaborations with Emory School of Medicine. Solenopsin A is an excellent inhibitor or angiogenesis. Solenopsin A is a lead compound for further development in our labs.
While drug design is a major focus of the Bowen research group, significant efforts over the years have been devoted to the application of molecular mechanics and quantum mechanics to conformational and structural problems. For example,
Over the years the Bowen group has been involved in computational chemistry software development. Presently, the Bowen group, in a fruitful collaboration with Semichem, Inc. is developing a new molecular mechanics program. Moreover, a successful 3D-QSAR program, MOSA, is being updated for commercial release.
Selected Publications (2003-2005)
1. Theoretical study of stereoselective reducgtion conrolled by NADH analogs. H. Zhong, J. P. Bowen J. Molecular Graphics and Modelling 2005, 24, 1-9.
2. Synthesis and Biological Evaluation of Aromatic Enones Related to Curcumin. T. R. Robinson, R. B. Hubbard, IV, T. Ehlers, J. L. Arbiser, D. J. Goldsmith, J. P. Bowen Biorg. & Med. Chem. 2005, 13, 4007-4013
3. Ab Initio and DFT Conformational Studies of Propanal, 2-Butanone, and Analogues Imines and Enamines. H. Zhong, E. L. Stewart, M. Kontoyianni, J. P. Bowen J. of Chem. Theory and Comput. 2005, 1, 230-238
4. Antiangiogenic Agents: Studies on Fumagillin and Curcumin Analogs..M S., T. P. Robinson, T. Ehlers, R. B. Hubbard, IV, J. L. Arbiser, D. J. Goldsmith, J. P. Bowen, Current Pharmaceutical Design 2005, 11, 357-373.
5. Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Analyses of Choline Acetyltransferase Inhibitors. V. Chandrasekaran,. G. B. McGaughey, C. J. Cavallito, J. P. Bowen J. Molecular Graphics and Modelling 2004, 23, 69-76.
6. Design, Synthesis, and Biological Evaluation of Angiogenesis Inhibitors: Aromatic Enone and Dienone Analogs of Curcumin. T. R. Robinson, T. Ehlers, R. B. Hubbard, IV, J. L. Arbiser, D. Goldsmith, J. P. Bowen Biorg. & Med. Chem. Let. 2003, 13, 115-117.
7. Molecular Mechanics (MM3) Development of a Zwitterion Force Field. K. N. Kirschner, A. H. Lewin, J. P. Bowen J. Comput. Chem 2003, 24, 111-128.
8. An Ab Initio Study of the Electrostatics of Protonated Amines: Application to the Molecular Mechanics (MM3) Force Field. J. Sorenson, A. H. Lewin, J. P. Bowen J. Mol. Struct. (THEOCHEM) 2003, 623, 145-158.