Bifunctional Chelating Agents for Gallium (III)

镓 (III) 双功能螯合剂

• 批准号: 6433349
• 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/6433349
• 关键词: chelating agents; chemical binding; chemical stability; chemical synthesis; gallium; immunoconjugates; ligands; radiochemistry; radionuclides; radiopharmacology

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

广泛的配位化学文献和Ga(III)同位素吸引人的物理特性继续刺激着我们对新配体的研究。新型双功能络合剂的合成和评价主要是为了隔离Ga(III)同位素，但这些配体也可以用于解决放射性药物和化疗应用中过渡金属的螯合问题。例如，双官能团的1，4，7-三氮杂环-N，N‘，N’‘-三乙酸(NOTA)在体内对Ga-66是一种非常稳定的捕捉剂。继续使用Ga-67作为俄歇发射器，对Ga(III)同位素的C功能化NOTA进行评估，事实证明，与大剂量In-111相比，这是有效的。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)三胺衍生物(TACHpyr)继续被研究用于化疗应用。正在进行的对作用模式的研究表明，相关的细胞毒性100%通过细胞凋亡发生，而P53也是无关的。破坏细胞铁的运输和储存机制显然是这种作用的一条途径。对Fe(II)[TACHpyr]络合物的研究也证明了配体对Fe(III)形成Fe(II)的反应氧化性质，然后通过氧化还原循环和Fenton化学进行循环。通过在TACHpyr的芳环上引入取代基来调节TACHpyr的吡啶给体的亲油性和电子性的研究已经开始。对这些配体形成的金属络合物的基本结构和稳定性的初步研究已经产生了初步的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来扰乱络合铁金属离子环境的电子性质。几种TACH配体的铜配合物正在研究中，这些配合物证明了在模型化合物中能够水解性地裂解DNA磷酸酯键，裂解质粒DNA，并在体外发挥显著的细胞毒性。初步研究表明，在小鼠系统中的最大耐受量和对铜(II)络合物重复治疗的肿瘤反应。在获得适当数量和一致性的络合物之前，正在计划进行进一步的研究，以扩大先前的结果，增加重复性，并确定这些金属络合物作为化疗药物的潜力。TACHpyr复合体也被评估为潜在的放射性药物。与自由配体相反，铜(II)络合物完全没有毒性。为此，初步评估了铜-67 TACHpyr络合物的体外稳定性，这可能与配体的芳环上的结构和取代基有关。计划与其他具有适当核医学性质的M(II)过渡金属一起对TACHpyr的铜(II)放射性金属络合物进行进一步的体内评估