Transition Metal Chelator for Radio- and Chemotherapy

新型螯合剂，基于顺，顺-1，3，5-三氨基环己烷（tach）作为一个平台，用于引入各种各样的金属结合官能团，继续探索放射性和化学治疗的应用。许多基于Tach的新型螯合剂已经被合成、表征和评价用于与各种过渡金属离子形成金属络合物。 具体地，tach（tachpyr）的三（吡啶基）三胺衍生物继续被研究用于化学治疗应用。这些配体破坏细胞铁转运和储存机制，激活细胞凋亡细胞毒性途径。用Fe（II）[tachpyr]进行的研究也证明了配体的反应性氧化性质，其中Fe（III）形成Fe（II），然后通过氧化还原循环和芬顿化学进行循环。初步的构效关系（SAR）研究表明，在TACHPyr的芳环上引入甲基取代基会影响所形成的金属配合物的基本结构和稳定性。初步的SAR信息表明吡啶基环的6-位的严重限制，但也增强了活性与3-位的取代，由于这提供了一个驱动力的氧化消除的配体与金属络合的同时。正在进行进一步的研究，以引入吸电子基团来扰乱螯合的Fe金属离子的环境的电子性质以及改变络合物的总电荷。与此同时，还计划进行修改以增加这些药剂的生物半衰期。 继续研究几种TACH配体的铜络合物，其表现出水解切割模型化合物中的DNA磷酸酯键、切割质粒DNA和在体外发挥显著细胞毒性的能力。虽然由于人员问题而搁置，但该项目的这一方面最近已重新启动，这些研究目前正在重新评估，然后再次转入小鼠肿瘤模型系统。 TACHpyr配合物也被评价为潜在的放射性药物沿着，与所有其他杂环六配位基于tach的配体一起具有64 Cu和67 Cu。对于tachpyr类似物以及其中吡啶基部分被咪唑替代的tachpyr类似物，已经注意到显著的体外稳定性。这些配体有效地transchelated铜（II）从与TETA，大环螯合剂在临床试验中采用，已被报道由于在体内transchelation不稳定性受损形成的复合物。计划进一步在体内评价这些配体的Cu（II）放射性金属络合物以及额外的六齿TACH衍生物，以充分评估它们的潜力，然后开始合成用于蛋白质修饰的双功能类似物。

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.