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

用于生物应用的金属烯二炔络合物环化动力学的开发、评估和完善

• 批准号: 2247314
• 负责人: Jeffrey Zaleski
• 金额: $ 57.5万
• 依托单位: Indiana University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2247314&HistoricalAwards=false
• 关键词: Development; Evaluation; Refinement; Metalloenediyne; Complex

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.

在该项目中，印第安纳大学化学系的杰弗里·扎莱斯基（Jeffrey Zaleski）教授在该项目中，印第安纳大学化学部的杰弗里·扎莱斯基（Jeffrey Zaleski）教授正在基于一种新的热热反应策略来开发结构和动态可调的分子，以抑制不希望的，基本细胞生长过程。 该方法的优点是，只有激活热和代理并存的位点，而其他所有站点仍然不受影响。 结构修饰还将结合组成可变性，以调整启动效果所需的加热水平。 结构的替代灵活性应允许现有的成像方法在体外或可能在体外均可在体外或可能的情况下跟踪这些分子。 该项目位于合成，无机和生物学研究领域的界面，为学生提供了各种培训环境，这些培训环境将进入这些领域的劳动力。 此外，整体计划将通过生产基于研究的动画学习工具来增强教育范围，以增加中学和高中的STEM（科学，技术，工程和数学）参与校园计划。Mental-nendeyneyne综合体（II）已显示出对肿瘤生长抑制的巨大希望，这可能是通过Bergman抑制的，可能是通过Bergman抑制了Bergman的bergman环化学对1,4-二聚体的cltea clladical clladical dirad cllad dna。 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表现出显着的半衰期范围（0.77-77 HR），这对于控制反应动力学非常有利。 但是，在生理条件和温度下，这些结构可能是不溶性的，它们的反应如此之快，以至于样品处理是一个挑战。 相反，他们的Fe（II）和Fe（III）亲戚在提供平行反应空间调谐作为取代基的函数的情况下显示出巨大的希望，但在更稳定的动力学平台上，以及可增强的溶解度。 Fe（iii）和GA（III）之间存在的同生主进一步打开了这些构建体，用于PET（正电子发射断层扫描）成像，从而为细胞底跟踪。 除了应用这些分子外，还将评估前向和伯格曼的机理速率，以将这些过程的真实速率常数评估为替代方案的函数，最终有望产生更好的潜在客户构造设计。这奖反映了NSF的法定任务，并通过使用基础的智力效果和宽阔的影响来评估NSF的法定任务，并以评估值得评估。