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: 6947126
• 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/6947126
• 关键词: antineoplastics; chelating agents; chelation therapy; chemical binding; chemical stability; chemical structure function; cyclic amine; cytotoxicity; drug design /synthesis /production; immunoconjugates; iron; iron metabolism; metal complex; neoplasm /cancer chemotherapy; pyridine; radiochemistry; radionuclides; radiopharmacology; tissue /cell culture

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.

以顺式，顺式-1,3,5-三氨基环己烷（tach）为基础的新型螯合剂，作为引入各种金属结合官能基团的平台，继续被探索用于放射治疗和化疗的应用。许多基于粘连的新型螯合剂已经被合成、表征和评价为与各种过渡金属离子形成金属配合物。具体来说，三（吡啶基）三胺衍生物塔克（tachpyr）继续被研究用于化疗的应用。这些配体破坏细胞铁转运和储存机制，激活凋亡细胞毒性途径。对Fe(II)[tachpyr]的研究也证明了配体的活性氧化性质，Fe（III）形成Fe(II)，然后通过氧化还原循环和芬顿化学循环。对tachpyr的亲脂性和电子性质的初步构效关系（SAR）研究表明，在tachpyr的芳环上引入甲基取代基会影响其金属配合物的基本结构和稳定性。初步的SAR信息表明吡啶基环的6位存在严重的局限性，但3位取代也增强了活性，因为这为金属络合的同时氧化消除配体提供了动力。引入吸电子基团来扰乱螯合铁金属离子环境的电子性质以及改变配合物的总体电荷的进一步研究正在进行中。与此同时，还计划进行修改，以增加这些制剂的生物半衰期。这项研究已经扩展到包括一种几何约束较小的三胺，trenn，以及所有先前评估的基于tach的化合物已经或正在合成以进行平行评估。制备了两种不同的双官能团tachpyr衍生物。它们的偶联化学已经建立，以及一种新的比色测定法，用于测定与蛋白质偶联的tachpyr和其他配体的数量。目前的计划包括使用赫赛汀偶联物进行体外细胞靶向和毒性研究，然后将其转化为基于动物的模型系统。几种TACH配体的铜配合物在模型化合物中表现出水解裂解DNA磷酸酯键的能力，裂解质粒DNA，并在体外发挥显著的细胞毒性，这些能力仍在继续研究中。该项目最近重新启动，这些研究现在正在重新评估，然后再次进入小鼠肿瘤模型系统。基于Cu（II）是血管生成的辅助因子，并且Cu（II）的消耗已被证明对肿瘤生长和血管发育有显著影响，TACHpyr螯合剂的整个文库也被评估为抗血管生成剂的效用。我们已经确定了几种重要的先导化合物，并正在筛选其他化合物，并在进行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。