""""""""The synthesis and evaluation of novel bifunctional chelating agents designed to sequester Ga(III) isotopes define the general scope of the project. While use of the C-functionalized 1,4,7-triazacyclononane-N,N',N''- triacetic acid (NOTA) as a sequestering agent for Ga-66 have shown this complex to be exceptionally stable in vivo, the of extensive chemical literature elucidating the coordination chemistry of Ga(III) prompted investigation into a new class of hexadentate ligands. Novel chelating agents, based on cis,cis-1,3,5-triaminocyclohexane (TACH) functioning as a platform for introducing a potentially wide variety of metal binding functional groups, continue to be synthesized, characterized, and evaluated for forming metal complexes with a variety of metal ions. The tris(pyridyl)triamine derivative (TACHpyr) continues to be investigated as a chemotherapeutic agent in a bladder cancer application, particularly as to the mode of action and involvement in cellular iron transport and storage mechanisms. Additionally, the novel series of TACH based substituted ethylene hexamine chelating agents were prepared and characterized. All formed complexes with both divalent and trivalent metals. Of particular interest has been the ability to alter lipophilicity by virtue of the alkyl groups that were introduced stereospecifically. Ongoing studies on fundamental structure and stability continues. Copper complexes of TACH ligands have also demonstrated their ability to hydrolitically cleave DNA phosphate ester bonds in model compounds, cleave plasmid DNA, and exert significant cytotoxicity in vitro that appears to be effective against an adriamycin resistant cell line. This effect also appears to be enhances under hypoxia and also appears in preliminary experiements to possess a radiosensitization component as well. These complexes also hydrolyse peptide bonds in model compounds. Further studies are being planned to thoroughly explore these preliminary results and to define the potential of these metal complexes as chemotherapeutics.""""""""
