Bifunctional Chelating Agents for Gallium (III)

广泛的化学文献的配位化学和有吸引力的物理特性的同位素镓（III）继续刺激我们的调查到新的配体的发展。 新型双功能螯合剂的合成和评价主要设计用于螯合Ga（III）同位素，但这些配体也可以评价以解决用于放射性药物和化学治疗应用的过渡金属的螯合。 例如，双官能1，4，7-三氮杂环壬烷-N，N ′，N ″-三乙酸（NOTA）已被证明是Ga-66在体内的异常稳定的螯合剂。 对于Ga（III）同位素的C-官能化NOTA的评估继续使用Ga-67作为俄歇发射体，当与大剂量的In-111相比时，Ga-67已被证明是有效的。基于顺式，顺式-1，3，5-三氨基环己烷（TACH）的新型螯合剂作为引入多种金属结合官能团的平台继续被开发。 许多基于TACH的螯合剂已经被合成、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的三（吡啶基）三胺衍生物（TACHPyr）继续被研究用于化学治疗应用。 对作用模式的持续研究表明，相关的细胞毒性100%通过细胞凋亡发生，也与p53无关。 细胞铁转运和储存机制的破坏显然是这种作用的途径。 对Fe（II）[TACHPyr]络合物的研究也证明了配体对Fe（III）的反应性氧化性质，形成Fe（II），然后通过氧化还原循环和芬顿化学进行循环。 通过在TACHPyr的芳环上引入取代基，开始了对TACHPyr的吡啶供体的亲脂性和电子性质进行调节的研究。 初步的研究与这些配体形成的金属配合物的基本结构和稳定性已经产生了初步的SAR信息，表明取代基位置的限制。进一步研究引入吸电子基团以扰乱螯合铁金属离子环境的电子性质。 目前正在研究几种TACH配体的铜络合物，这些TACH配体表现出水解切割模型化合物中的DNA磷酸酯键、切割质粒DNA以及在体外发挥显著细胞毒性的能力。初步研究表明，在小鼠系统中的最大耐受剂量和肿瘤的反应，重复治疗的Cu（II）络合物。 在合适的量和一致性的配合物的可用性之前，正在计划进一步的研究以扩展先前的结果，增加再现性，并确定这些金属配合物作为化疗剂的潜力。 TACHpyr复合物也被评价为潜在的放射性药物。 注意到Cu（II）络合物完全没有毒性，与游离配体相反。 为此，Cu-67 TACHPyr络合物的初步评价表明，显著的体外稳定性可能与配体芳环上的结构和取代基相关。 计划沿着TACHPyr的Cu（II）放射性金属络合物与具有合适核药物特性的其他M（II）过渡金属的进一步体内评价

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