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.

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。此后，这项研究已扩大到包括几何约束较小的三胺、tren，并且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。已经制备了两种不同的双功能tachpyr衍生物。它们的缀合化学以及用于确定与蛋白质缀合的tachpyr和其他配体数量的新型比色测定法已经建立。目前的计划包括使用赫赛汀缀合物进行体外细胞靶向和毒性研究，然后转化为基于动物的模型系统。几种 TACH 配体的铜复合物表现出水解裂解模型化合物中的 DNA 磷酸酯键、裂解质粒 DNA 的能力，以及在体外发挥显着细胞毒性的研究仍在继续。该项目最近已重新启动，这些研究在再次进入小鼠肿瘤模型系统之前正在接受重新评估。TACHpyr 螯合剂的整个库也已基于 Cu 的抗血管生成剂的效用进行了评估。 (II) 是血管生成的辅助因子，Cu(II) 的消耗已被证明对肿瘤生长和脉管系统发育具有显着影响。我们已经确定了几种重要的先导化合物，并且正在筛选其他化合物并在进入动物模型系统之前大规模地重新评估先导化合物。