Transition Metal Chelator for Radio- and Chemotherapy

以顺，顺-1，3，5-三氨基环己烷(TACH)为平台引入多种金属结合官能团的新型螯合剂，在放射和化疗方面的应用仍在不断探索。许多基于TACH的新型络合剂已被合成、表征和评价，用于与多种过渡金属离子形成金属络合物。具体地说，TACH的三(吡啶基)三胺衍生物(Tachpyr)继续被研究用于化疗应用。这些配体扰乱了细胞铁的运输和储存机制，激活了一条凋亡细胞毒性的途径。对Fe(II)[Tachpyr]的研究也证明了配体的反应氧化性质，Fe(III)形成Fe(II)，然后通过氧化还原循环和Fenton化学循环。初步的结构活性关系(SAR)研究表明，在TACHPYR的芳环上引入甲基取代基，影响了形成的金属络合物的基本结构和稳定性。初步的SAR信息表明，吡啶环的6位受到严重限制，但由于3位取代的活性增强，这提供了在金属络合的同时氧化消除配体的驱动力。进一步的研究正在进行中，目的是引入电子吸引基团来扰乱螯合的铁金属离子环境的电子性质，以及改变络合物的总电荷。与此同时，也在计划进行修改，以增加这些制剂的生物半衰期。自那以后，这项研究已经扩大到包括几何限制较少的三胺，特雷恩，所有先前评估的基于TACH的化合物已经或正在合成进行平行评估。合成了两种不同的双功能速比衍生物。它们的共轭化学已经建立，并建立了一种新的比色法来测定速尿和其他与蛋白质结合的配体的数量。目前的计划包括用赫赛汀结合物进行体外细胞靶向和毒性研究，然后翻译到动物模型系统。几种TACH配体的铜配合物显示出能够在模型化合物中水解性断裂DNA磷酸酯键，切割质粒DNA，并在体外发挥显著的细胞毒性作用，这一点仍在继续研究。该项目最近被重新启动，这些研究正在重新评估，然后再被应用到小鼠肿瘤模型系统中。整个TACHpyr螯合剂库也被评估了它们作为抗血管生成剂的有效性，因为铜(II)是血管生成的辅助因子，而且铜(II)的缺乏已被证明对肿瘤生长和血管发育有显著影响。我们已经确定了几种重要的先导化合物，并正在筛选更多的化合物，并在进入动物模型系统之前对先导化合物进行更大规模的重新评估。

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. This study has since been expanded to include a less geometrically constrained triamine, tren, and all of the previously evaluated compounds based on tach have been or are being synthesized for a parallel evaluation. Two different bifunctional tachpyr derivatives have been prepared. Their conjugation chemistry has been established as well as a novel colorometic assay for determining the number of tachpyr and other ligands conjugated to protein. Current plans include in vitro cell targeting and toxicity studied with a Herceptin conjugate followed by translation to animal based model systems.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. This project has recently been reactivated and these studies are now being re-evaluated prior to being carried forward again into murine tumor model systems.The entire library of TACHpyr chelating agents has also been evaluated for their utility as anti-angiogenesis agents based upon that Cu(II) is a co-factor of angiogenesis and that depletion of Cu(II) has been shown to have marked effects on tumor growth and vasculature development. We have identified several substantial lead compounds and are in the process of both screening additional compounds and re-evaluating the lead compounds on a larger scale before proceeding to animal model systems.