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.

在这个项目中，由化学部的化学结构，动力学机制-B计划资助，印第安纳州大学化学系的Jeffrey Zaleski教授正在开发结构和动态可调的分子，用于抑制基于新的热诱导反应策略的不期望的基本细胞生长过程。 该方法的优点是，只有热和代理共存的网站被激活，而所有其他网站保持不受影响。 结构修饰还将结合组成可变性，以努力调整引发该效应所需的加热水平。 结构的取代灵活性应允许现有的成像方法用于在体外或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，为将进入这些领域的学生提供多样化的培训环境。 此外，该总体计划将加强教育推广，通过制作基于研究的动画学习工具，增加初中和高中STEM（科学、技术、工程和数学）在校园项目中的参与。铂（II）的金属-烯二炔配合物已经显示出相当大的肿瘤生长抑制前景，可能是通过伯格曼环化形成1，4-二基双自由基物种，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小时），这对于控制反应动力学来说是个好兆头。 然而，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，它们的Fe（II）和Fe（III）亲属显示出相当大的前景，用于提供作为取代基的函数的平行反应空间调谐，但在更稳定的动力学平台上，沿着增强的溶解度。 Fe（III）和Ga（III）之间存在的同构性进一步为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，正向和逆向伯格曼反应的机械速率也将被评估，以解开这些过程的真实速率常数作为替代的函数，最终有望产生更好的铅结构designs.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。