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.

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。 几种TACH配体的铜络合物在模型化合物中证明了能够水解性地裂解DNA磷酸酯键，裂解质粒DNA，并在体外表现出显著的细胞毒性。由于人员问题被搁置，该项目的这一方面最近已重新启动，目前正在重新评估这些研究，然后再将其带入小鼠肿瘤模型系统。 TACHpyr络合物也被认为是一种潜在的放射性药物，与所有其他杂环六配位的TACH配体64Cu和67Cu一起被评估为潜在的放射性药物。已经注意到速效类似物以及其中吡啶部分被咪唑取代的速效类似物具有显著的体外稳定性。这些配体有效地从与Teta形成的络合物中交换铜(II)，Teta是临床试验中使用的一种大环络合剂，据报道，由于体内交换不稳定，Teta受到了损害。计划在体内进一步评估这些配体的铜(II)放射性金属络合物以及其他六齿TACH衍生物，以便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。