Novel chelating agents, based on cis,cis-1,3,5-triaminocyclohexane (tach) as a platform for introducing a wide variety of metal binding functional groups, continue to be explored for both radio- and chemotherapeutic applications. Numerous novel chelating agents based upon tach have been synthesized, characterized, and evaluated for forming metal complexes with a variety of transition metal ions. Specifically, tris(pyridyl)triamine derivatives of tach (tachpyr) continue to be investigated for chemotherapeutic applications. These ligands disrupt cellular iron transport and storage mechanisms activating a pathway for apoptotic cytotoxicity. Studies with Fe(II)[tachpyr] have also demonstrated the reactive oxidative nature of the ligand with Fe(III) forming Fe(II) and then cycling through redox cycles and Fenton chemistry. Preliminary structure activity relationship (SAR) studies into tuning lipophilicy and electronic nature of the pyridine donors of tachpyr have indicated that the introduction of methyl substituents onto the aromatic rings of TACHpyr inpact the fundamental structure and stability of the metal complexes formed. Preliminary SAR information indicates severe limitations of the 6-position of the pyridyl ring, but also enhancement of activity with substitution at the 3-position due to this providing a driving force for oxidative elimination of the ligand concurrent with metal complexation. Further studies to introduce electron-withdrawing groups to perturb the electronic nature of the environment of the chelated Fe metal ion as well as to alter the overall charge of the complex are ongoing. In parallel, modifications are also being planned to increase the biological half-life of these agents. 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 continue to be investigated. While on hold due to personnel issues, this aspect of this project has recently been reactivated and these studies are now being re-evaluated prior to beingcarried forward again into murine tumor model systems. The TACHpyr complex has also been evaluated as a potential radiopharmaceutical along with all of the other heterocyclic hexacoordinating tach based ligands with 64Cu and 67Cu. Significant in vitro stability has been noted for the tachpyr analogs as well as a tachpyr analog wherein the pyridyl moiety was replaced with imidazole. These ligands efficiently transchelated Cu(II) from the complex formed with TETA, a macrocyclic chelating agent employed in clinical trials that has been reported compromised due to in vivo transchelation instability. Further in vivo evaluation of the Cu(II) radio-metal complexes of these ligands as well as additional hexadentate TACH derivatives are planned to fully evaluate their potential prior to embarking of syntheses of bifunctional analogs for protein modification.
