Modern biochemical techniques have identified a large number of peptides having potent pharmacological activities. However, since peptides are not usually orally active and suffer from short half lives in vivo, their direct utilization as drugs is not generally feasible. In addition, the interactions of many peptides with their macromolecular targets (receptors, enzymes, antibodies) will depend on the adoption of a particular conformation. Accordingly, the design of conformationally restricted peptides and the partial replacement of peptides with bioisosteric units have become contemporary goals of medicinal chemistry. In turn, the realization of these ideas requires the development of new synthetic strategies.
We are currently involved in several projects along the lines of this general theme. One such project is the design and synthesis of novel Freidinger lactams. We have also developed a series of linkers for the constraint of peptide strands into b-turns. These compounds are often able to selectively populate particular conformations, which is important for designing in biological activity. Concidentally (or is it?!), both projects involve the use of our oxaziridine chemistry and so fit in well with our synthetic methodology interests.
Our continuing efforts in this area involve both additional conformational studies and the synthesis of pharmacologically active versions of these compounds.
Download the Chem 3D Files for more details:
Freidinger Lactam | trans dimethyl | cis dimethyl
Lead References
1. Structural Analysis of b-Turn Mimics Containing a Substituted 6-Aminocaproic Acid Linker. Kitagawa, O.; Vander Velde, D.; Dutta, D.; Morton, M.; Takusagawa, F.; Aubé, J. J. Am. Chem. Soc. 1995, 117, 5169-5178.
2. Aubé, J. In Advances in Amino Acid Mimetics and Peptidomimetics; Abell, A., Ed.; JAI Press: Greenwich, 1997; Vol. 1, pp 193-232. A review article.
3. Stereoselective Synthesis of Freidinger Lactams Using Oxaziridines Derived from Amino Acids. Wolfe, M. S.; Dutta, D.; Aubé, J. J. Org. Chem. 1997, 62, 654-663.
4. Effect of Progressive Benzyl Substitution on the Conformations of Aminocaproic Acid-Cyclized Dipeptides. MacDonald, M.; Vander Velde, D.; Aubé, J. J. Org. Chem., 2001, 66, 2636-2642.
For More Information Contact:
Department of Medicinal Chemistry
4070 Malott Hall
Tel: 785-864-4495
FAX: 785-864-5326
Internet: jaube@ku.edu
