Transition Metal Chelator for Radio- and Chemotherapy

用于放疗和化疗的过渡金属螯合剂

• 批准号: 6756264
• 负责人: MARTIN W BRECHBIEL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6756264
• 关键词: chelating agents; chemical binding; chemical stability; chemical structure function; chemical synthesis; chemotherapy; copper; cyclic amine; cytotoxicity; gallium; heavy metals; immunoconjugates; iron; ligands; metal complex; radiochemistry; radionuclides; radiopharmacology

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.

基于顺式的新型螯合剂，CIS-1,3,5-三氨基苯甲酰己烷（TACH），作为引入各种金属结合官能团的平台，继续用于放射性和化学治疗应用。已经合成，表征和评估了与各种过渡金属离子形成金属配合物的许多新型螯合剂。 具体而言，TACH（TACHPYR）的Tris（吡啶基）三胺衍生物继续研究化学治疗应用。这些配体破坏了细胞铁的传输和储存机制，激活了凋亡细胞毒性的途径。 Fe（II）[Tachpyr]的研究还证明了配体与Fe（III）形成Fe（II）的反应性氧化性质，然后通过氧化还原周期和Fenton Chemistry循环。初步结构活性关系（SAR）研究tachpyr的吡啶捐赠者调整亲脂性和电子性质，表明将甲基取代基引入Tachpyr的芳香环上，构成了形成的金属络合物的基本结构和稳定性。初步SAR信息表明吡啶基环6位的严重限制，但由于这提供了氧化消除与金属络合的配体同时消除配体的驱动力，因此在3位处加强了活性。进一步的研究介绍吸电子基团，以扰动螯合金属离子环境的电子性质以及改变复合物的整体电荷。同时，还计划修改这些药物的生物半衰期。 几种旋转配体的铜复合物表明在模型化合物中水解裂解DNA磷酸酯键，裂解质粒DNA并在体外发挥明显的细胞毒性的能力继续进行研究。尽管由于人员问题而被搁置，但该项目的这一方面最近已重新激活，并且现在对这些研究重新评估，然后再次将其转发到鼠肿瘤模型系统中。 tachpyr复合物也已被评估为潜在的放射性药物以及所有其他杂环六链球化的基于64cu和67cu的基于旋钮。对于速度类似物以及tachpyr类似物，已经注意到了显着的体外稳定性，其中吡啶基部分被咪唑代替。这些配体从用TETA形成的络合物（一种临床试验中使用的大环螯合剂形成的复合物）有效地旋转了Cu（II），据报道，由于体内递移不稳定性而受到损害。计划进一步评估这些配体的Cu（II）射电 - 基准复合物以及其他六齿状TACH衍生物，以便在启动双功能类似物的合成蛋白质修饰之前完全评估其潜力。