Lipophilic/Oligomeric Tetraazamacrocycles: The Development of New Diagnostic/Therapeutic Agents

In work initially supported by the American Cancer Society and the North Carolina Biotechnology Center, we are developing new therapeutic/diagnostic agents for diseased tissue using lipophilic and oligomeric derivatives of saturated azacrown macrocycles. Saturated tetraazamacrocycles have proven to be versatile macrocyclic ligands capable of forming stable, inert complexes with a variety of biomedically important metal ions.

Our progress in this area is marked by the synthesis and study of a class of isopropyl and isobutyl-appended macrocycles and their metal complexes that inhibit the growth of mouse leukemia cells (L1210) in micromolar to submicromolar concentrations. Working in collaboration with Drs. Joseph and Ann Cory at the East Carolina University School of Medicine, we have been able to probe lipophilic macrocycle structure/anticancer property relationships in vitro.  An in vitro screening (National Cancer Institute, 60 human tumor cell lines) of a representative compound revealed enhanced activity toward specific types of tumor cells.  We are now designing and synthesizing second generation macrocycles to further enhance biological activity.

We are also synthesizing oligomeric derivatives of tetraazamacrocycles with the goal of preparing monoclonal antibody bioconjugates for the site-specific delivery of a potentially large number of metal ions per antibody with minimal loss in protein activity. We have developed iterative synthetic procedures that merge the areas of peptide and dendrimer synthesis for the preparation of macrocyclic arrays using selectively-protected azacrowns as building blocks. Our general synthetic methods will have direct application in the synthesis of azacrown dendrimers.

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