The extensive chemical literature of the coordination chemistry and the attractive physical characteristics of the isotopes of Ga(III) continue to stimulate our investigation into the development of new ligands. The synthesis and evaluation of novel bifunctional chelating agents are primarily designed to sequester Ga(III) isotopes, but these ligands may also be evaluated to address the chelation of transition metals for both radiopharmaceutical and chemotherapeutic applications. For example, the bifunctional 1,4,7-triazacyclononane-N,N',N''- triacetic acid (NOTA) has been shown to be an exceptionally stable sequestering agent for Ga-66 in vivo. Evaluation of C-functionalized NOTA for Ga(III) isotopes continues with use of Ga-67 as an Auger emitter which has proven to be efficacious when compared to large doses of In-111. Novel chelating agents, based on cis,cis-1,3,5-triaminocyclohexane (TACH) functioning as a platform for introducing a wide variety of metal binding functional groups, continue to be exploited. Numerous chelating agents based upon TACH have been synthesized, characterized, and evaluated for forming metal complexes with a variety of transition metal ions. Specifically, the tris(pyridyl)triamine derivative of TACH (TACHpyr) continues to be investigated for chemotherapeutic applications. Ongoing investigation into the mode of action has indicated that the associated cytotoxicity occurs 100% by apoptosis and is also p53 indifferent. Disruption of cellular iron transport and storage mechanisms are clearly a pathway for this action. Studies with the Fe(II)[TACHpyr] complex have also demonstrated the reactive oxidative nature of the ligand towards Fe(III) forming Fe(II) and then cycling through redox cycles and Fenton chemistry. Studies into tuning the lipophilicy and electronic nature of the pyridine donors of TACHpyr have been initiated through the introduction of substituents onto the aromatic rings of TACHpyr. Initial studies on the fundamental structure and stability of the metal complexes formed with these ligands have produced preliminary SAR information indicating limitations of substituent position. Further studies to introduce electron-withdrawing groups to perturb the electronic nature of the environment of the chelated Fe metal ion. Copper complexes of several TACH ligands that demonstrated the ability to hydrolytically cleave DNA phosphate ester bonds in model compounds, to cleave plasmid DNA, and to exert significant cytotoxicity in vitro, are being investigated. Preliminary studies demonstrated a maximum tolerated dose in murine systems and a tumor response to repeated treatments with the Cu(II) complex. Pending availability of the complex in suitable amount and consistency, further studies are being planned to expand the prior results, increase reproducibility, and define the potential of these metal complexes as chemotherapeutics. The TACHpyr complex has also been evaluated as a potential radiopharmaceutical. The Cu(II) complex was noted to completely lack toxicity, as opposed to the free ligand. To this end, preliminary evaluation of the Cu-67 TACHpyr complex indicated significant in vitro stability that could be correlated to structure and substituents on the aromatic rings of the ligand. Further in vivo evaluation of the Cu(II) radio-metal complex of TACHpyr is planned along with other M(II) transition metals that possess suitable nuclear medicinal properties
