Development, Evaluation and Refinement of Metalloenediyne Complex Cyclization Kinetics for Biological Applications

在这个由化学学部化学结构、动力学和机理b项目资助的项目中，印第安纳大学化学系的Jeffrey Zaleski教授基于一种新的热诱导反应策略，正在开发结构和动态可调的分子，用于抑制不需要的基本细胞生长过程。该方法的优点是只有热和剂共存的部位被激活，而所有其他部位不受影响。结构修改还将包括成分的变化，以调整启动效果所需的加热水平。结构的替代灵活性应该允许现有的成像方法用于在体外甚至可能在体内条件下跟踪这些分子。该项目位于合成、无机和生物研究空间的界面，为即将进入这些领域的学生提供多样化的培训环境。此外，该计划还将加强教育推广，通过制作研究性动画学习工具，提高初中和高中学生对校园项目的STEM（科学、技术、工程和数学）参与度。Pt（II）的金属-烯二炔配合物显示出相当大的抑制肿瘤生长的希望，可能是通过伯格曼环化到1,4-二基双自由基导致DNA切割。通过配体修饰和辅助配体取代，它们在室温下的反应动力学也显示出显著的半衰期范围（0.77 ~ 77 hr），这为控制反应动力学提供了良好的前景。然而，在生理条件和温度下，这些结构可能是不溶的，它们的反应如此之快，以至于样品处理是一个挑战。相反，它们的Fe（II）和Fe（III）亲族表现出相当大的希望，可以作为取代基的函数提供平行反应空间调整，但在更稳定的动力学平台上，以及增强的溶解度。存在于Fe（III）和Ga（III）之间的等结构进一步为PET（正电子发射断层扫描）成像和亚细胞跟踪打开了这些结构。除了这些分子的应用之外，还将评估正向和反向伯格曼反应的机制速率，以解开这些过程的真实速率常数，作为取代的函数，最终有望产生更好的先导结构设计。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

In this project, funded by the Chemical Structure, Dynamics & Mechanisms-B Program of the Chemistry Division, Professor Jeffrey Zaleski of the Department of Chemistry at Indiana University is developing structurally and dynamically tunable molecules for inhibition of undesired, fundamental cell growth processes based on a new heat-induced reaction strategy. The advantage of the methodology is that only sites where heat and agent coexist are activated, while all other sites remain unaffected. Structural modification will also incorporate compositional variability in an effort to tune the level of heating required to initiate the effect. The substitutional flexibility of the structures should allow for existing imaging methods to be used to track these molecules under in vitro or possibly even, in vivo, conditions. The project rests at the interface of synthetic, inorganic, and biological research space, providing a diverse training environment for students that will enter the workforce in these areas. Moreover, the ensemble plan will enhance educational outreach to increase middle and high school STEM (science, technology, engineering and mathematics) engagement in campus programs through production of research-based animation learning tools.Metal-enediyne complexes of Pt(II) have shown considerable promise for tumor growth inhibition, presumably via Bergman cyclization to 1,4-diyl diradical species that lead to DNA cleavage. Through ligand modification and ancillary ligand substitution, their reaction kinetics at room temperature also demonstrate a remarkable half-life range (0.77-77 hr), which bodes well for controlling reaction kinetics. However, under physiological conditions and temperatures, these structures may be insoluble and their reactions so fast that sample handling is a challenge. Conversely, their Fe(II) and Fe(III) relatives show considerable promise for delivering parallel reaction space tuning as a function of substituents, yet on a more stable kinetic platform, along with enhanced solubility. The isostructuralism that exists between Fe(III) and Ga(III) further opens these constructs up for PET (positron emission tomography) imaging and thus sub-cellular tracking. In addition to the application of these molecules, mechanistic rates for forward and retro-Bergman reactions will also be evaluated to disentangle true rate constants for these processes as a function of substitutions which is ultimately expected to produce better lead construct designs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.