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.

新型螯合剂以 cis,cis-1,3,5-三氨基环己烷 (tach) 为平台，引入多种金属结合官能团，在放射治疗和化疗应用中不断得到探索。已经合成、表征和评估了许多基于 tach 的新型螯合剂，以与各种过渡金属离子形成金属配合物。 具体而言，tach (tachpyr) 的三(吡啶基)三胺衍生物继续在化疗应用中进行研究。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。 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，然后通过氧化还原循环和芬顿化学进行循环。对调节 tachpyr 吡啶供体的亲脂性和电子性质的初步结构活性关系 (SAR) 研究表明，在 TACHpyr 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 信息表明吡啶环 6 位的严重限制，但 3 位取代也增强了活性，因为这为配体的氧化消除与金属络合同时提供了驱动力。引入吸电子基团以扰乱螯合铁金属离子环境的电子性质以及改变络合物的总电荷的进一步研究正在进行中。与此同时，还计划进行修改以延长这些药物的生物半衰期。 几种 TACH 配体的铜配合物表现出在模型化合物中水解裂解 DNA 磷酸酯键、裂解质粒 DNA 以及在体外发挥显着细胞毒性的能力，这些都在继续研究中。虽然由于人事问题而搁置，但该项目的这方面最近已重新启动，这些研究现在正在重新评估，然后再次转移到小鼠肿瘤模型系统中。 TACHpyr 配合物与所有其他带有 64Cu 和 67Cu 的杂环六配位 tach 配体一起也被评估为潜在的放射性药物。已经注意到tachpyr类似物以及其中吡啶基部分被咪唑取代的tachpyr类似物具有显着的体外稳定性。这些配体有效地从与 TETA 形成的复合物中转螯合 Cu(II)，TETA 是一种临床试验中使用的大环螯合剂，据报道由于体内转螯合不稳定性而受到损害。计划对这些配体的 Cu(II) 放射性金属络合物以及其他六齿 TACH 衍生物进行进一步的体内评估，以在开始合成用于蛋白质修饰的双功能类似物之前充分评估它们的潜力。